Dietary supplement and related method

ABSTRACT

A composition including a unique combination of fruits, vegetables, herbs, and optionally vitamins, minerals and specialty ingredients. The composition can include a fruit ingredient, a vegetable ingredient and an herbal ingredient, wherein the fruit ingredient is at least one of pomegranate and citrus bioflavonoids, wherein the vegetable ingredient, is at least one of asparagus, lutein, lycopene and watercress, and wherein the herbal ingredient is at least one of basil, oregano and rosemary. The composition can be administered to subjects to correct a dietary deficiency of phytochemicals and other nutrients, improve plasma concentrations of antioxidant nutrients, and increase the activity of genetic mechanisms for DNA repair and stability.

This is a continuation-in-part application of U.S. application Ser. No.10/915,784, filed Aug. 11, 2004, which is a continuation-in-partapplication of U.S. application Ser. No. 10/360,789, filed May 7, 2002(now U.S. Pat. No. 6,989,161), which is a continuation-in-partapplication of U.S. application Ser. No. 09/878,377, filed Jun. 12, 2001(now U.S. Pat. No. 6,511,675), which claims benefit of U.S. ProvisionalApplication No. 60/210,746, filed Jun. 12, 2000, all of which are herebyincorporated by reference.

BACKGROUND OF THE INVENTION

The present invention relates to a composition and method for correctinga dietary deficiency, including an inadequacy of phytochemicals,vitamins and minerals.

Many people fail to practice healthy eating habits, such as consuming anadequate quantity and variety of food to meet U.S. Recommended DietaryAllowances. Only 22% of the subjects of a National Cancer InstituteStudy consumed the recommended daily number of dietary servings offruits and vegetables—despite the fact that the recommended dietaryintake of fruits and vegetables is well-known. For example. TheCalifornia Daily Food Guide; Dietary Guidelines for California,California Department of Health Services (1990) recommends that eachperson consume at least five to nine servings of fruit and vegetablesper day, including one serving of a vitamin A-rich deep green or darkorange fruit or vegetable, and at least one serving of a vitamin C-richfruit or vegetable. Additionally, it is well reported that each personshould consume at least 3 servings per week of vegetable protein in theform of legumes, nuts, or seeds. Some researchers suggest that a targetof 400 grams (13 ounces) of fruits and vegetables is a sensible goal forthe optimal quantity to be consumed daily. In terms of variety, it isrecommended that persons should eat at least three different colors offruits and vegetables daily.

The benefits of consuming a sufficient amount and variety of fruits andvegetables are many. For example, consuming fruits and vegetables hasbeen shown to reduce the risk of a variety of degenerative diseases. Ina prospective cohort study of 41,837 postmenopausal women, theassociation of fruit and vegetable consumption with lung cancer risk wasinvestigated. The researchers found that the risk of lung cancer wasapproximately halved when the consumption of fruits and vegetablesincreased from 24 or less servings to an excess of 48 servings per week.Similarly, the risk of lung cancer was approximately halved when theconsumption of green leafy vegetables, including spinach and parsleysources, increased from one or fewer servings to six or more servingsper week. Steinmetz, K. et al., “Vegetables, Fruit, and Lung Cancer inthe Iowa Women's Health Study,” Cancer Res. 53:536-43 (1993). Anotherstudy found that an increased intake of fresh tomatoes (a major sourceof lycopene) was associated with a pattern of protection for all sitesof digestive tract cancer. Stahl, W. et al., “Lycopene: A BiologicallyImportant Carotenoid for Humans?” Arc. Biochem. Biophys. 336:1-9 (1996).

In addition to fruits and vegetables, herbs also provide healthbenefits. For example, the herb, rosemary, contains antioxidants such ascarnosol, which may play a preventive role in cholesterol oxidation.Likewise, the herb, basil is known for its antioxidant activity. Likefruits and vegetables, however, the dietary intake of beneficial herbsis unsatisfactory.

Further research has shown that the typical U.S. diet is lacking inphytochemicals. Phytochemicals generally refer to plant-derivedcompounds which, when taken daily in combination with vitamins andminerals, provide improved cardiovascular and bone health, an improvedantioxidant profile, decreased free radical damage, and overallenhancement of the body's natural defense system.

The typical diet, especially the U.S. diet, includes an inadequateamount and variety of fruits, vegetables and herbs, as well as thephytochemicals and associated antioxidants present in these materials. Atypical diet is similarly deficient in necessary vitamins and mineralsassociated with fruits and vegetables. Although conventionalmultivitamins can supplement western diets with needed vitamins andminerals, many of these multivitamins fail to provide phytochemicalsthat target free radicals in the body and thereby improve theantioxidant profile of the supplement.

SUMMARY OF THE INVENTION

The present invention provides a composition including a uniquecombination of fruit vegetable, and herb dehydrates, concentrates, orextracts; and optionally vitamins, minerals and specialty ingredients tocorrect a dietary deficiency of those materials.

The composition of the present invention provides substantial healthbenefits. For example, in one embodiment, it can support the health ofpeople who consume a nutritionally deficient diet; improve antioxidantand nutrient status; replenish serum nutrient and phytochemical levelsas a result of inadequate diets to levels associated with decreased riskof certain degenerative disease states; minimize free radical damagethat occurs as a result of normal aging processes and exposure toenvironmental stresses; and/or improve the status of specific biomarkersindicative of optimal health, namely homocysteine, lipid byproducts,mineral status and glutathione peroxidase.

In a more specific embodiment, the composition of the present inventioncan provide β-carotene, α-lipoic acid, selenium, and vitamins C and E,which improve the antioxidant profile of a person. Increased levels offolic acid and vitamins E target and improve cardiovascular health.Calcium, magnesium, and vitamin D targets and improves bone health. Bvitamins improve energy metabolism. The compositions according to theinvention can provide 100% of the U.S. Recommended Daily Intake of allvitamins and most minerals. The composition also can provide a varietyof phytochemicals to produce a diverse antioxidant profile.

In an even more specific embodiment, the composition can include acombination of fruit, vegetable and herbal ingredients, wherein thefruit ingredients are selected from acerola, apple, blueberry, citrusbioflavonoids, cranberry, grape skin, plum, and pomegranate; wherein thevegetable ingredients are selected from asparagus, alfalfa, brassica,kale, lutein, lycopene, and watercress; and wherein the herbalingredients are selected from basil, oregano, parsley, sage androsemary. These ingredients can be concentrated, for example they may beextracted from raw ingredients. Optionally, the fruit ingredients,vegetable ingredients and herbal ingredients can be present in thecomposition in a ratio of about 3.5:1:1 by weight. Specialtyingredients, such as alpha lipoic acid and inositol can be added to thecomposition.

In yet another embodiment, the composition can include at least onefruit ingredient selected from the group consisting of citrusbioflavonoids and pomegranate, and optionally at least one of acerola,apple, blueberry, cranberry, grape skin, plum and raspberry; at leastone vegetable ingredient selected from the group consisting ofasparagus, lutein, lycopene, and watercress, and optionally at least oneof alfalfa, brassica, and kale; and at least one herbal ingredientselected from the group consisting of basil, oregano and rosemary, andoptionally at least one of parsley and sage.

In another embodiment, a method is provided for enhancing the immunesystem, as well as treating and/or reducing die risk of DMA damage ofthe human body comprising administering an effective amount of acomposition including at least one fruit ingredient selected from thegroup consisting of citrus bioflavonoids and pomegranate, and optionallyat least one of acerola, apple, blueberry, cranberry, grape skin, andplum; at least one vegetable ingredient selected from the groupconsisting of asparagus, lutein, lycopene, and watercress, andoptionally at least one of alfalfa, brassica, and kale; and at least oneherbal ingredient selected from the group consisting of basil, oreganoand rosemary, and optionally at least one of parsley and sage.

These and other objects, advantages and features of the invention willbe more readily understood and appreciated by reference to the detaileddescription of the invention and the drawings. It is to be understoodthat both the foregoing general description and the following detaileddescription are exemplary and explanatory only and are not restrictiveof the invention as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph depicting the effect the composition has on Vitamin Clevels.

FIG. 2 is a graph depicting the effect the composition has on betacarotene levels.

FIG. 3 is a graph depicting the effect the composition has on Vitamin B₆levels.

FIG. 4 is a graph depicting the effect the composition has on VitaminB₁₂ levels.

FIG. 5 is a graph depicting the effect the composition has on Folatelevels.

FIG. 6 is a graph depicting the effect the composition has onhomocysteine levels.

FIG. 7 is a graph depicting the numbers of genes related to DNA orchromatin maintenance or repair that were modulated by consumption ofthe composition.

FIGS. 8A and 8B which are a diagram (FIG. 8A) and a graph (FIG. 8B)depicting decreased oxidative stress with treatment using thecomposition of the present invention as indicated by decreasedconcentration of 2-hydroxybutarate.

FIGS. 9A and 9B are a diagram (FIG. 9A) and a graph (FIG. 9B) depictingdecreased oxidative stress with treatment using the composition of thepresent invention as indicated by decreased concentration of5-oxoproline.

FIG. 10 is a graph depicting the change in plasma beta-caroteneconcentration after treatment.

FIG. 11 is a graph depicting the change in plasma folate concentrationafter treatment.

FIG. 12 is a graph depicting the change in plasma vitamin B6concentration after treatment.

FIG. 13 is a graph depicting the change in plasma vitamin B12concentration after treatment.

FIG. 14 is a graph depicting the change in plasma homocysteineconcentration after treatment.

FIG. 15 is a graph depicting the change in DNA damage after treatment.

FIG. 16 is a graph depicting the change in baseline expression activityof genes associated with DNA maintenance genes after treatment.

DETAILED DESCRIPTION OF THE INVENTION

I. Overview

In general, the invention relates to a composition comprising fruits,vegetables and herbs. In one embodiment, the composition can include afruit ingredient, a vegetable ingredient and an herbal ingredient,wherein the fruit ingredient is at least one of pomegranate and citrusbioflavonoids, wherein the vegetable ingredient is at least one ofasparagus, lutein, lycopene and watercress, and wherein the herbalingredient is at least one of basil, oregano and rosemary. Thecomposition can also be combined with a known therapy that can impactchromatin stability thereby limiting the detrimental effects of suchtherapy.

The following fruit ingredients also can be present in the composition:acerola, apple, blueberry, cranberry, grape skin, and plum. Further, thefollowing vegetable ingredients also can be present in the composition:alfalfa, brassica, and kale. Finally, the following herbal ingredientsalso can be present in the composition: sage and parsley.

The composition has a synergistic effect in the treatments discussedherein. Thus, the components of the composition together are moreeffective that individually. Additionally, the composition modulates,and more specifically as discussed herein up-regulates, genes associatedwith chromatin stability, examples of which are discussed in the figuresand examples.

Example of genes involved in telomere maintenance include, but are notlimited to, Ku, Cdc 13 protein, the catalytic subunit EST2, and threeother genes, EST1, EST3, EST4/CDC13, MRE11, RAD50, XRS2 (yeast)/NBS1,p53, hTERT, ATM, TRF2, the TERF family of genes.

The composition of the present invention can either treat or reduce theoccurrences/risks of chromatin damage, and thus support genomestability, by increasing the expression of genes involved in identifyingand correcting damage to DNA as well as associated protein structures(i.e., chromatin). The reduction in the occurrence/risk of chromatindamage includes any statistically significant reduction that correlatesto a biological response or outcome. These genes control activitiesincluding, but not limited to, repair of base pair mismatches, repair ofdouble strand breaks, or other maintenance, repair or supervisory roles.Most damage is caused by oxidation, nutrient deficiency, radiation ortoxins. There are four main types of damage to DNA due to endogenouscellular processes or exogenous insult such as ultraviolet radiation:oxidation of bases [e.g. 8-oxo-7,8-dihydroguanine (8-oxoG)] andgeneration of DNA strand interruptions from reactive oxygen species,alkylation of bases (usually methylation), such as formation of7-methylguanine, 1-methyladenine, O6 methylguanine hydrolysis of bases,such as deamination, depurination and depyrimidination, mismatch ofbases, due to errors in DNA replication, in which the wrong DNA base isstitched into place in a newly forming DNA strand, or a DNA base isskipped over or mistakenly inserted. There are four major DNA-repairpathways in human cells: mismatch repair, nucleotide-excision repair(NER), base-excision repair (BER), and double-strand-break (DSB) repair.The NER pathway mainly removes bulky DNA adducts. The BER pathway isresponsible for removal of oxidized DNA bases that may ariseendogenously or from exogenous agents. The DSB pathway is responsiblefor repairing double-strand breaks caused by a variety of exposures,including ionizing radiation, free radicals, and telomere dysfunction.Examples of such genes include, but are not limited to ERCC, RAD2, RAD6,RAD7, RAD18, RAD23, RAD51, RAD54, CDC7, CDC8, CDC9, MAG1, PHR1, DIN1,DDR48, RNR1, RNR2, RNR3, UB14, repB, repD and APE. These genes areimpacted by the composition of the present invention can modulate any ofthe types of damage disclosed above.

The composition can thus be used to treat diseases associated with DNArepair problems including, but not limited to, xeroderma pigmentosum,Cockayne syndrome, trichothiodystrophy, Werner's syndrome, Bloom'ssyndrome and ataxia telangiectasia. All of which are associated withimproper repair of DNA.

The composition can also be used to affect/modulate the function ofmitochondria function-specific genes, examples of such genes areprovided in Table 8 below. These genes generally fall into fourcategories. First, genes for mitochondrial transcription/translation,examples of which include, but are not limited to, MTRF1L, which isinvolved in mitochondrial translational machinery, GFM2, which is aprotein involved in protein elongation, MRPL3, which is a mitochondrialribosomal protein, TOMM20, which is a central component of the receptorcomplex responsible for the recognition and translocation ofcytosolically synthesized mitochondrial preproteins and together withTOM22 functions as the transit peptide receptor at the surface of themitochondrion outer membrane and facilitates the movement of preproteinsinto the TOM40 translocation pore. COX15, which is predominantly foundin tissues characterized by high rates of oxidative phosphorylation(OxPhos) involved in heme biosynthesis, POLG2, mtDNA that is replicatedaccurately by DNA polymerase gamma, and MRPS10, which is part ofmitochondrial 28S Ribosomal protein. Second, genes for mitochondrialstructure examples of such genes include, but are not limited to, DNMIL,which is critical for maintenance of mitochondrial morphology, OPA1,which is a major organizer of the mitochondria); inner membrane and isrequired for the maintenance of cristae integrity, MFN1, which is anessential transmembrane GTPase, which mediates mitochondrial fusion(MFN1 acts independently of the cytoskeleton.), BNIP3, which providesregulation of mitochondrial permeability, COX18, which is required forthe insertion of integral membrane proteins into the mitochondrial innermembrane and is essential for the activity and assembly of cytochrome coxidase and plays a central role in the translocation and export of theC-terminal part of the COX2 protein into the mitochondrial intermembranespace, and DNM1L, which functions in mitochondrial and peroxisomaldivision probably by regulating membrane fission and enzyme hydrolyzingGTP that oligomerizes to form ring-like structures and is able toremodel membranes. Third, miscellaneous mitochondrial proteins examplesof such genes include, but are not limited to, WWOX, a tumor suppressorgene, PPIF, for protein folding, CoQ9, 10GB, which is involved in thefinal steps in the synthesis of CoQ, SLC25A37, which is a mitochondrialiron transporter that specifically mediates iron uptake in developingerythroid cells, thereby playing an essential role in heme biosynthesis,ABCB7, which is involved in the transport of heme from the mitochondriato the cytosol, and SLC25A36, which is a transporter for mitochondria.Fourth, genes for mitochondrial enzymes examples of such genes include,but are not limited to, SDHD, which is part of the respiratory chain,ATPAF1 enzymes which are critical for generation of ATP, NARS2, IARS2,EARS2, LARS2, HARS2, which are enzymes involved in the production ofamino acid, ASN, ILE and GLN, LEU and HIS respectively, HIBADH, which isan enzyme providing succinyl coA for TCA cycle, ACADSB, which is anenzyme catalyzing one of the steps in fatty acid beta oxidation, MIB1,which is a E3 ligase necessary for protein ubiquitnation (deletionlethal), BCKDHB and ACAD8, for the generation of succiny Co A for TCA,AFG3L2, which is a AAA protease protecting against oxiative stress,PEO1, which is a DNA helicase, critical for lifetime maintenance ofmtDNA integrity and to maintain mtDNA copy number, HK2 (Hexokinase 2),and HADHB, which is involved in fatty acid beta-oxidation.

The composition can also be combined with a known therapy to create acombinatorial therapy. This can primarily be used in instances where theknown therapy has known detrimental side effects that impact DNAstability, such as chemotherapeutics and radiotherapeutics. Othercompounds can also be used that negatively impact DNA repair andstability.

The invention also relates to a method for correcting a diet-induceddeficiency of fruits, vegetables and herbs, and the nutrients present insuch materials. The composition of the present invention additionallycan contain phytochemicals, vitamins, and minerals known to improve thebody's natural defenses against oxidants, free radicals, and diseases.

II. Composition and Method of Manufacture

The composition can include a combination of fruit, vegetable, herbaland other ingredients that provide significant health benefits. Thefollowing tables illustrate representative daily amounts of suitablefruits, vegetables, herbs, vitamins, and minerals which can be includedin the composition. The dosages and methods of administration can bevaried as desired from application to application. For example, Dosage Arepresents a range of dosages of the respective ingredients that issuitable for purposes of the present, invention. Dosage B represents adosage of a particular embodiment. The unit “mg” in Tables 1-5 meansthat that the amount recited is given in the number of, e.g.,milligrams, provided in a two-tablets per day dosage, unless otherwisenoted, e.g., “JU” is recited. Thus, to determine the amount of aspecific ingredient per single tablet, the amount recited in therespective tables must be halved.

TABLE 1 Fruit Ingredient Dosage A, mg/day Dosage B, mg/day AcerolaPowder 50-500  300 Apple extract 25-1000 50 Citrus Bioflavanoids 25-1000100 Grape skin extract 25-1000 50 Plum extract 25-1000 50 Cranberryextract 25-1000 50 Pomagranate 5-500 25 Blueberry extract 25-1000 50

The citrus bioflavonoids are commercially available from Access BusinessGroup International LLC of Ada, Mich. This ingredient can be in aconcentrate form, and can include, but are not limited to, naringen,hesperidin, narirutin, diosmin, rutin, tangeretin, diosmetin,neohesperidin, nobiletin, and quercetin.

TABLE 2 Vegetable Ingredient Dosage A, mg/day Dosage B, mg/day Asparagus25-1000 50 Alfalfa 25-1000 70 Brassica 25-1000 50 Kale 20-1000 75Lycopene 0.1-100   2 Lutein esters 0.1-100   2 NUTRILITE Watercress5-500 28

NUTRILITE watercress is available from Access Business GroupInternational LLC. The Brassica and/or kale can be in dehydrated,powdered form. As used herein the Brassica ingredient may include anymaterial derived from plants in the Brassicae family, for example,broccoli. The lutein esters used in the composition can be of the typesold under the name Xangold 10% beadlets, which is available from CognisNutrition & Health of Cincinnati, Ohio. The lycopene used in thecomposition can be of the type sold under the name Lycobeads 5%, whichis available from H. Reisman Corp. of Orange, N.J.

TABLE 3 Vegetable Ingredient Dosage A, mg/day Dosage B, mg/day Basilextract 25-1000 50 Rosemary extract 25-1000 50 Sage 5-500 25 Oreganoextract 25-1000 50 NUTRILITE Parsley 5-500 25

NUTRILITE parsley is available from Access Business Group InternationalLLC. The composition can also include ingredients in addition to thefruit, vegetable and herbal ingredients noted above. For example,suitable vitamins for use in the compositions and methods of the presentinvention can include, vitamin A, vitamin B1, vitamin B2, vitamin B6,vitamin B12, niacin/niacinamide, pantothenic acid, folic acid, biotin,choline, vitamin C, vitamin D, and vitamin E. Table 4 below includes asuitable vitamin profile.

TABLE 4 Vitamin Profile Dosage B, Ingredient Dosage A, mg/day mg/dayVitamin C from Acerola 20-100 60 Powder Ascorbic Acid (C) 100-700  440Vitamin A from Beta Carotene 1000-10,000 IU 7500 IU Biotin 0.01-4   0.300 Pantothenic Acid from Cal  5-300 50 Pan Gran Choline 10-400 50Folic Acid 0.01-10   0.8 Inositol  5-100 25 Vitamin E 10-5000 IU  150 IUMixed Tocopherols  5-300 50 Niacin/Niacinamide  5-300 40 Pyridoxine (B6)10-100 15 Riboflavin (B2)  1-100 12.75 Thiamine (B1)  1-100 11.25Vitamin A from Acetate 100-10,000 IU 2500 IU Vitamin B12 0.01-50   0.045Vitamin D3 10-2000 IU 400 IU Yeast, Standardized@  5-350 60 (source of100% RDA Bs)

In addition to the vitamins listed above, minerals for use in thecompositions and methods of the present invention include, for example,boron, calcium, chromium, copper, iodine, magnesium, manganese,molybdenum, potassium, selenium, vanadium, and zinc. Other vitamins andminerals may also be used. Table 5 below includes a mineral profilesuitable for the composition of the present invention.

TABLE 5 Mineral Profile Ingredient Dosage A, mg/day Dosage B, mg/dayCalcium 100-2000 750 Chromium 0.01-5    0.120 Copper 0.01-5    2 Iodine0.001-5    0.15 Magnesium  10-1000 300 Manganese 1-20 5 Molybdenum0.001-75    0.075 Potassium  5-300 80 Selenium 0.001-5    0.100 Zinc1-50 15

With the ingredients of Tables 1-3, and optionally the ingredients ofTables 4-5, the composition of the present invention can provide asignificant portion of, and in many cases exceed, the recommended dailyrequirement for a variety of vitamins and minerals. Tables 6 and 7 belowillustrate the potency of the composition, when taken in the above dailyamounts, in terms of percentages of the daily requirements for thelisted vitamins and minerals.

TABLE 6 Vitamin Amount/Day % Daily Value Vitamin A (75% as β- 10,000200% Carotene), IU Vitamin C, mg 500 833% Vitamin D, IU 400 100% VitaminE, IU 150 500% Niacin/Niacinamide, mg 40 200% Vitamin B₆, mg 15 750%Vitamin B₁₂, mcg 45 750% Folic Acid, mcg 800 200% Biotin, mcg 300 100%Pantothenic Acid, mg 50 500%

TABLE 7 Minerals Amount/Day % Daily Value Calcium, mg 750  75%Magnesium, mg 300  75% Iodine, mcg 150 100% Potassium, mg 80  2% Copper,mg 2 100% Zinc, mg 15 100% Manganese, mg 5 100% Chromium, mcg 120 100%Selenium, mcg 100 143% Molybdenum, mcg 75 100%

Additional specialty ingredients which can be used in the compositioninclude, for example, methyl sulfonyl methane (MSM), α-lipoic acid (10mg/day), catechins, polyphenols, flavanoids, lycopene, lutein, yeast,inositol, and para-aminobenzoic acid (PABA).

The composition of the present invention can be formulated using anypharmaceutically acceptable form of respective fruit concentrates,vegetable concentrates, herb concentrates, phytochemicals, vitamins,minerals, and other nutrients, including their salts. The compositionscan be formulated into tablets, powders, gels, or liquids (a tablet, forthe purposes of the present invention and as used throughout theapplication disclosure, refers to any form of a solid oral dosage,including but not limited to tablets, caplets, capsules, powders, etc.).The compositions can be formulated as powders, for example, for mixingwith consumable liquids such as milk, juice, water, or consumable gelsor syrups for mixing into other liquids or foods. The compositions canalso be formulated with other foods or liquids to provide pre-measuredcompositional foods, for example, single-serving bars. Flavorings,binders, protein, complex carbohydrates, and the like can be added asneeded.

According to one aspect of the invention, the composition isadministered as three separate tablets, all three of which areadministered twice a day; however, the composition may be administeredin other forms and unit dosages as desired.

The composition of the present invention will be illustrated by, but isnot intended to be limited to, the following examples.

EXAMPLE 1

Three tablets may be prepared to provide a) fruit, vegetable and herbalingredients, b) vitamins and c) minerals. The first tablet includes thefruit, vegetable and herbal ingredients of Tables 1-3. The amount ofeach ingredient in this first tablet is half of the amount listed in theDosage B of the Tables, as the table-listed amount is the amount presentin two such tablets. The first tablet may also include carriers andother tableting aids such as silicon dioxide, magnesium oxide, calciumcarbonate, croscarmellose sodium, microcrystalline cellulose andmagnesium stearate in amounts that may be varied for purposes well knownto those of skill in the art.

The second tablet includes vitamins of Table 4. The amount of eachingredient in this second tablet is half of the amount listed in theTable, as the table-listed amount is the amount present in two suchtablets. The second tablet may also include carriers and other tabletingaids such as microcrystalline cellulose, calcium carbonate,croscarmellose sodium, magnesium stearate, and silicon dioxide.

The third tablet includes minerals of Table 5. The amount of eachingredient in this third tablet is half of the amount listed in theTable, as the table-listed amount is the amount present in two suchtablets. The third tablet may also include carriers and other tabletingaids such as microcrystalline cellulose, calcium carbonate,croscarmellose sodium, magnesium stearate, and silicon dioxide.

The three tablets, when administered twice a day, complete the gap inphytochemicals that is present in the typical diet.

EXAMPLE 2

The following examples relate to methods of preparing the above threetablets. The ingredients are the same as those referred to above inTables 1-5. For purposes of the following examples, however, tabletsincluding the fruit, vegetable and herbal ingredients from Tables 1-3are referred to as “Tablet 1”; tablets including the vitamin ingredientsfrom Table 4 are referred to as “Tablet 2”; and tablets including themineral ingredients from Table 5 are referred to as “Tablet 3.” It isnoted that other methods for preparing the tablets and other suitabledelivery vehicles can be used as desired.

Tablet 1

Mixed tocopherols, D-alpha-tocopherol (succinate), and silicon dioxide(NF fine powder) are passed through a SWECO separator equipped with a 20mesh screen into a 100 cubic foot PK blender. The ingredients areblended for ten minutes Magnesium oxide (D.C. heavy), Acerolaconcentrate, citrus bioflavonoids complex, plum extract, apple extract,rosemary extract, basil extract, grape skin extract, cranberry extract,kale powder, asparagus extract, blueberry extract, parsley dehydrate,oregano extract, sage extract, pomegranate extract, and inositol arepassed through a SWECO separator equipped with a 20 mesh screen into a100 cubic foot PK blender. The ingredients are blended for ten minutes.

Lycopene (5%), lutein ester (beadlets), mixed tocopherols, calciumcarbonate (granular), croscarmellose sodium and microcrystallinecellulose (silicified) are passed through a SWECO separator equippedwith a 20 mesh screen directly into a 100 cubic foot PK blender. Themixture is blended for ten minutes. Next, magnesium stearate (Kosher) ispassed through a SWECO separator equipped with a 20 mesh screen directlyinto a 100 cubic foot PK blender. The ingredients are blended for anadditional five minutes. The resulting mixture is discharged into totesor supersacks, and compressed into tablets.

Tablet 2

Acerola concentrate, microcrystalline cellulose (silicified) and alphalipoic acid are passed through a SWECO separator equipped with a 20 meshscreen directly into a 100 cubic foot P.K. blender. The ingredients areblended for ten minutes. Next, the following ingredients are passedthrough a SWECO separator equipped with a 20 mesh screen directly intothe 100 cubic foot PK blender: thiamine mononitrate (97%), riboflavin,niacinamide, biotin trituration (1%), vitamin B12 (1.1%), calciumpantothenate granular, folic acid, pyridoxine HCl (95%), and cholinebitartrate. The ingredients are blended for ten minutes. Next, thefollowing items are passed through a SWECO separator equipped with a 20mesh screen directly into the 100 cubic foot PK blender; beta carotene(beadlets), vitamin D3 (beadlets), yeast (standardized) and vitamin A(acetate). The mixture is blended for an additional ten minutes.

Next, the following ingredients are passed through a SWECO separatorequipped with a 20 mesh screen directly into the 1.00 cubic foot PKblender: ascorbic acid (97%), calcium carbonate (granular),croscarmellose sodium, d-alpha-tocopherol succinate, silicon dioxide (NFfine powder). The mixture is blended for an additional ten minutes.

Next, magnesium stearate (Kosher) is passed through a SWECO separatorequipped with a 20 mesh screen directly into the 100 cubic foot PKblender. The mixture is blended for an additional five minutes. Theresulting mixture is discharged into totes or supersacks, and compressedinto tablets.

Tablet 3

Zinc amino acid chelate, mixed tocopherols and silicon dioxide (NF finepowder) are passed through a SWECO separator equipped with a 20 meshscreen into a 100 cubic foot PK blender. The ingredients are blended forten minutes. Co-processed alfalfa concentrate/microcrystallinecellulose/calcium carbonate, selenium yeast, microcrystalline cellulose,copper amino acid chelate, manganese amino acid chelate, potassiumiodide trituration, chromium amino acid chelate, molybdenum amino acidchelate, brassica dehydrate, watercress dehydrate and croscarmellosesodium are passed through a SWECO separator equipped with a 20 meshscreen directly into a 100 cubic foot PK blender. The ingredients areblended for ten minutes.

Potassium chloride, magnesium oxide (D.C. heavy) and calcium carbonate(granulation) are passed through a SWECO separator equipped with a 20mesh screen directly into a 100 cubic foot PK blender. The ingredientsare blended for ten minutes. Next, magnesium stearate (Kosher) is passedthrough a SWECO separator equipped with a 20 mesh screen directly into a100 cubic foot PK blender. The ingredients are blended for an additionalten minutes. Next, magnesium stearate (Kosher) is passed through a SWECOseparator equipped with a 20 mesh screen directly into the 100 cubicfoot PK blender. The mixture is blended for an additional live minutes.The resulting mixture is discharged into totes or supersacks, andcompressed into tablets.

EXAMPLE 3

The clinical study was an independent Review Board-approved,double-blind, placebo-controlled, parallel-groups study.

Subjects

Subjects were 120 healthy adult Japanese-Americans in California andHawaii Subjects were ethnically Japanese (both parents and fourgrandparents ethnically Japanese) and ate a mostly Japanese diet

Treatment

Subjects took either composition or placebo as directed (12 tablets aday) for 8 weeks. The composition is the same formula as is currentlymarketed in Japan under the Alticor name of Triple X™. All products werecoated and provided in coded foil packs to preserve double-blindedness.

Outcome Measures

There were four main categories of outcome measures; (1) plasmaconcentrations of a representative water-soluble antioxidant nutrient[vitamin c], and a representative fat-soluble antioxidant nutrient [betacarotene], (2) plasma concentrations of the “anti-homocysteine triad”vitamin B6, vitamin B12, and folate, as well as plasma concentrations ofhomocysteine, (3) nutrigenomic mechanisms of genomic stability, and (4)plasma metabolomic profile changes.

Analyses for plasma nutrient and homocysteine concentrations were basedon blood samples obtained from 120 subjects (60 treated with Triple X,and 60 treated with Placebo), at baseline, Week 4, and Week 8.

Nutrigenomic analyses were based on blood samples obtained from 14subjects (7 treated with Triple X, and 7 treated with Placebo) atbaseline and Week 2.

Statistics

Plasma nutrient and homocysteine change score results were assessed withindependent-groups t-test for between-groups comparisons. A P valuesmaller than 0.05 was considered significant.

Nutrigenomic data were first analyzed with paired t-tests within thecomposition-treated group only to identify which from among 44,000 genesmeasured showed a significant change in expression level followingtreatment. A P value smaller than 0.05 was considered significant. A Qvalue (false discovery rate) of 0.4 was used to control for falsepositive findings. This analysis identified about 2,000 genes, whichwere then examined for biologically relevant patterns of change.

Results from the clinical study were as follows. Compared to subjectstaking Placebo, subjects taking composition showed increased levels offolate, vitamin B6, vitamin B12, and vitamin C, as well as decreasedlevels of homocysteine, all within 4 weeks of treatment, with resultsmaintained at 8 weeks. Metabolomic analyses indicate decreased oxidativestress. Nutrigenomic analyses indicate increased genomic integrity andtumor suppressor mechanisms, homocysteine metabolism, resistance tooxidative stress and lipid peroxidation.

Clinical interpretation of nutrigenomic data revealed the unexpectedfinding that about 150 genes, each known to function to support genomicstability (via chromatin maintenance, damage detection, and repair),were significantly increased in the Triple X group compared to theplacebo group. Subsequent analysis of these genes in the Placebo-treatedgroup showed no change following Placebo treatment. Compared tobaseline, consumption of the composition of the present invention led tostatistically significant increases in the expression of genes relatedto DNA maintenance, replication, or repair (FIG. 7).

Clinical interpretation of metabolomic data revealed the unexpectedfindings that consumption of Triple X led to significant decreaseincreases in 2-hydroxy bury rate, a metabolite related to oxidativestress (FIG. 9), as well as a trend towards a decrease in 5-oxoproline,also a metabolite related to oxidative stress (FIG. 10). This shows thatthe consumption of the composition can lead to increased plasmaconcentration of antioxidant nutrients, increased expression ofchromatin maintenance and repair genes, decreased homocysteine, anddecreased metabolomic indicators of oxidative stress.

EXAMPLE 4

Clinical testing was conducted to confirm the efficacy of thecomposition of the present invention. It was expected that consumptionof the composition would: correct dietary deficiencies ofphytochemicals; improve the amount of antioxidants in the body; decreasefree radical damage; increase plasma vitamin, mineral and phytochemicalconcentrations; and improve plasma and systemic antioxidant capacity,among other things.

Inclusion criteria for this study were healthy men and women, from 18 to80 years of age, who consume fewer than 12 items found on theRecommended Foods Checklist per week. These subjects are selected afteradministration of a food frequency questionnaire and application of theRecommended Foods Score (RFS). The RFS consists of 23 foods, 14 of whichare fruits and vegetables, that when consumed on a weekly basis havebeen associated with reduced mortality. This was demonstrated in acohort study of 42,254 women. Those with a mean RFS of 16.0 (highestquartile) had an all-cause mortality relative risk of 0.69 compared tothose with a mean RFS of 6.4 (lowest quartile) who have an all-causemortality relative risk. It was noted that those in the highest quartileconsumed significantly more calories (131%), fiber (200%), Vitamin C(230%), folate (181%), and pro-Vitamin A carotenoids (253%) compared tothose in the lowest quartile.

The clinical study encompassed a double-blind (i.e. to subjects andinvestigators) study of 120 subjects over a six-week period. During thesix-week trial, subjects were told to consume three tablets, either thecomposition, or a placebo, twice a day, such as morning and evening. Thesubjects were tested by taking blood and urine samples and performingthe following assays: total polyphenols, plasma ORAC (Oxygen RadicalAbsorption Capacity), CP450 enzyme induction, cytokinesis blockmicronucleus assay, comet assay, bioenergetics assay, urinary bileacids, B6, B12, folate, Vitamin C, homocysteine, alpha and gamatocopherols, beta-carotene, C-reactive protein and urinary 8-epiprostaglandins F2α, which were tested at baseline, two weeks, four weeksand six weeks into the study. Improvement, and thus, efficacy of thecomposition, was measured based on: plasma concentrations of vitamins,minerals and phytochemicals; plasma and systemic antioxidant capacity;detoxification capacity; cellular energy dynamics; genomic stability;other risk factors and subjective effects.

It was expected that the results of the study would show that followingsix weeks of composition consumption, subjects would have significantlyincreased plasma levels of alpha tocopherols, B12, B6, folate, VitaminC, and other antioxidants, which indicates an improvement in the amountof antioxidants in the body and which is associated with a correction ofdietary deficiencies in vitamins, nutrients and phytochemicals, and/or adecrease in free radical damage, as well as increased genomic stability(i.e., decreased DNA damage) among other things.

Results from the clinical study were as follows. Compared to subjectstaking Placebo, subjects taking the composition showed increased plasmaconcentrations of Beta Carotene, Alpha-Tocopherol, Folate, and VitaminsB6 and B12. Subjects taking composition also showed significantlyreduced homocysteine, as well as decreased DNA damage as indicated bythe cytokinesis micronucleus block assay. This shows that theconsumption of the composition can increase plasma concentrations ofantioxidant nutrients, decrease homocysteine, and decrease DNA damage.

The above descriptions are those of the preferred embodiments of theinvention. Various alterations and changes can be made without departingfrom the spirit and broader aspects of the invention as defined in theappended claims, which are to be interpreted in accordance with theprinciples of patent law including the doctrine of equivalents. Anyreferences to claim elements in the singular, for example, using thearticles “a,” “an,” “the,” or “said,” is not to be construed as limitingthe element to the singular.

TABLE 8 ADH5 \alcohol Removal of S-nitrosoglutathione and Anti-dehydrogenase thus controls its levels as well as levels Nitrosative 5(class III), of nitrosylated proteins. Protects against stress activitychi nitrosative stress. Low amounts of this gene polypeptide\“” enzymeor absence can increase whole cell nitrosylation and tissue damage andsusceptibility to bacteria. TXNL1 thioredoxin- TXNL1 acts as an effectorof oxidants or Anti-oxidant like 1 a redox sensor activity gene TXNRD3thioredoxin Thioredoxin reductases (EC 1.6.4.5), Anti-oxidant reductase3 such as TXNRD3, are selenocysteine activity gene (sec)-containingflavoenzymes that maintain thioredoxins, small proteins that catalyzeredox reactions, in the reduced state using the reducing power of NADPH,sec residue of TXNRD1 serves as a sensor of reactive oxygen species.UHRF2 \ubiquitin-like, Absence of this gene makes cells moreAnti-oxidant containing sensitive to X rays, UV light and activity genePHD and hydroxyurea RING finger domains, 2\“” VPS8 vacuolar VPS3, VPS8and PEP7 genes to rescue Anti-oxidant protein sorting lethal effects ofoxidative damage activity gene 8 homolog (S. cerevisiae) resulted fromthe overexpression of these genes. PAFAH2 \platelet- Membranephospholipids are Anti-oxidant Detoxification activating susceptible tooxidation, which is activity gene activity factor involved in variouspathological gene acetylhydrolase processes such as inflammation, 2, 40kDa\“” atherogenesis, neurodegeneration, and aging. One enzyme that mayhelp to remove oxidized phospholipids from cells is intracellular typeII platelet- activating factor acetylhydrolase (PAF- AH (II)), whichhydrolyzes oxidatively fragmented fatty acyl chains attached tophospholipids. Overexpression of PAF- AH (II) in cells or tissues waspreviously shown to suppress oxidative stress- induced cell death. ME2\malic enzyme The primary role of malic enzyme, Anti-oxidant 2, NAD(+)-however, may be to generate reduced activity gene dependent, NADP+ forbiosynthesis rather than to mitochondrial\ form an intermediate ofcarbohydrate “” catabolism. NADPH provides the reducing equivalents forbiosynthetic reactions and for oxidation-reduction involved inprotection against the toxicity of ROS PON2 paraoxonase 2 The encodedprotein is ubiquitously Anti-oxidant expressed in human tissues,membrane- activity gene bound, and may act as a cellular antioxidant,protecting cells from oxidative stress. Hydrolytic activity againstacylhomoserine lactones, important bacterial quorum-sensing mediators,suggests the encoded protein may also play a role in defense responsesto pathogenic bacteria. IVNS1ABP influenza virus Protects cells fromcell death induced by Anti-viral NS1A binding actin destabilization;Protects neurons protein from dendritic spines and actin filamentsdamage induced by the actin- destabilizing cytochalasin B whenoverexpressed. May be a component of the cellular splicing machinerywith a role in pre-mRNA splicing; may mediate the inhibition of splicingby NS/influenza virus NS1A protein. Highly present in neutrophil ILF3\interleukin Nuclear factor of activated T-cells Anti-viral enhancer(NFAT) is a transcription factor required activity gene binding factorfor T-cell expression of interleukin 2. 3, 90 kDa\“” NFAT binds to asequence in the IL2 enhancer known as the antigen receptor responseelement 2. In addition, NFAT can bind RNA and is an essential componentfor encapsidation and protein priming of hepatitis B viral polymerase.NFAT is a heterodimer of 45 kDa and 90 kDa proteins, the larger of whichis the product of this gene. The encoded protein, which is primarilylocalized to ribosomes, probably regulates transcription at the level ofmRNA elongation, required for IL2 mRNA stabilization. Anti-viralactivity SRPK2 SFRS protein SRPK1 and SRPK2 in HBV replicationAnti-viral kinase 2 and found that both of them could activity genesuppress HBV replication by reducing the packaging efficiency of thepgRNA without affecting the formation of the viral core particles. PTX3\pentraxin- anti-viral activity Anti-viral related gene, activity generapidly induced by IL- 1 beta\“” RIPK2 receptor- Anti-viral responseAnti-viral interacting activity gene serine- threonine kinase 2 SMARCE1\SWI/SNF Suppression of hepatitis B virus (HBV) Anti-viral related,matrix replication, a causative agent for chronic activity geneassociated, hepatitis, is an effective approach to actin controllingdisease progression. Host dependent factors have a significant effect onviral regulator of replication efficiency and need to be chromatin,better characterized.. Cellular subfamily e, transcription modulatorSMARCE1 binds member 1\“” to HBV core promoter containing naturallyoccurring deletions and represses viral replication. Transcriptionalcoactivator cooperating with nuclear hormone receptors to potentiatetranscriptional activation, he SWI/SNF chromatin remodeling complexesare evolutionarily conserved multimeric enzymatic machines that alterthe nucleosomal structure using energy derived from ATP hydrolysis (34).Ample experimental evidence suggests that the SWI/SNF complexes playimportant roles in fundamental cellular processes such as transcription,replication, and the repair of chromatin TLR7 toll-like TLR7-specificagonists activate Anti-viral receptor 7 plasmacytoid DCs (pDCs) and Bcells activity gene and induce mainly IFN-a and IFN- regulatedcytokines, the natural ligands of TLR7 and TLR8 were identified assingle-stranded RNA (ssRNA), single stranded (ss)RNA viruses [eithervesicular stomatitis virus (VSV; a rhabdovirus) or influenza virus (anorthomyxovirus)] stimulate type I IFN responses through TLR7. ZNF175zinc finger OTK18 was copiously expressed in Anti-viral protein 175macrophages following HIV type I activity gene infection and diminishedprogeny virion production. A mechanism for this antiretroviral activitywas by suppression of HIV type 1 Tat-induced viral long terminal repeatpromoter activity. BNIP2 BCL2/adenovirus Adenovirus E1B 19-kD proteinprotects Anti-viral E1B against cell death induced by viral activitygene 19 kDa infection and certain external stimuli. interacting protein2 CDKN1A \cyclin- is an endogenous cellular component in Anti-viraldependent stem cells that provides a molecular activity gene kinasebarrier to HIV-1 infection., anti-viral inhibitor 1A (p21, Cip1)\“”CREBZF CREB/ATF The neuronal host cell factor-binding Anti-viral bZIPprotein Zhangfei inhibits herpes simplex activity gene transcriptionvirus replication. factor ELF1 E74-like factor ELF-1 belongs to a subsetof Ets factors Blood vessel 1 (ets domain that regulatevascular-specific gene development transcription expression during bloodvessel gene factor) development. NUS1 nuclear Acts as a specificreceptor for the N- Blood vessel undecaprenyl terminus of Nogo-B, aneural and development pyrophosphate cardiovascular regulator. Able togene synthase 1 regulate vascular remodeling and homolog (S. cerevisiae)angiogenesis. Its similarity with UPP synthetase proteins suggests thatit may act as a scaffold for the binding of isoprenyl lipids and/orprenylated proteins. Nogo-B receptor localizes with the ligand Nogo-Bduring VEGF and wound healing angiogenesis in vivo, mediates chemotaxisin a heterologous expression system and chemotaxis, and 3D tubeformation in native endothelial cells. Thus, identification of thisreceptor may lead to the discovery of agonists or antagonists of thispathway to regulate vascular remodeling and angiogenesis. CLIC4 chlorideCLIC4 is involved in formation of the Blood vessel intracellular bloodvessel lumen. Blood vessel development channel 4 formation. Chloridechannel or a gene regulator or accessory subunit of other proteins thatcould provide the pore- forming function. SGPP1 sphingosine-Sphingosine-1-phosphate (S1P) is a highly Blood vessel 1-phosphatebioactive lipid that exerts numerous biological development phosphatase1 effects both intracellularly as a second messenger gene andextracellularly by binding to its G-protein- coupled receptors of theendothelial differentiation gene family (S1P receptors-(1-5)).Intracellularly, at least two enzymes, sphingosine kinase and S1Pphosphatase, regulate the activity of S1P by governing thephosphorylation status of S1P. It is now well established that S1P isthe natural ligand for specific G protein-coupled receptors (GPCRs),hereafter referred to as S1PRs. To date, five members, EDG-1/S1P1,vascular smooth muscle cells and pericytes to migrate around arteriesand capillaries and properly reinforce them.angiogenesis. DMTF1 cyclin DDMP1 is a pivotal tumor suppressor for Bone health binding myb- bothhuman and murine lung cancers. like DMP1 is essential for normalpostnatal transcription chondrogenesis and subsequent factor 1osteogenesis-bone LEMD3 LEM domain LEMD3 is involved in both BMP (seeBone Health containing 3 112264) and TGF-beta (190180) Activity Genesignaling. an integral protein of the inner nuclear membrane, bindsSmad2 and Smad3 and antagonizes transforming growth factor-betasignaling. Involved in multiple bone disorders. MBTPS1 \membrane- Site-1protease (S1P) has an essential Bone Health bound function in theconversion of latent, Activity Gene transcription membrane-boundtranscription factors to factor their free, active form. In mammals,peptidase, abundant expression of S1P in site 1\“” chondrocytes suggestsan involvement in chondrocyte function. Catalyzes the first step in theproteolytic activation of the sterol regulatory element-binding proteins(SREBPs). Other known substrates are BDNF and ATF6. RPS6KA3 \ribosomalRsk2 plays an important role in neuronal Bone Health protein S6plasticity. RSK2 is required for Activity Gene kinase, osteoblastdifferentiation and function. 90 kDa, Rsk2-null mice develop progressivepolypeptide osteopenia due to impaired osteoblast 3\“” function andnormal osteoclast differentiation. BCAT1 \branched This gene encodes thecytosolic form of Cell health chain the enzyme branched-chain amino acidMaintenance aminotransferase transaminase. This enzyme catalyzes Gene 1,the reversible transamination of cytosolic\“” branched-chain alpha-ketoacids to branched-chain L-amino acids essential for cell growth. CEPT1choline/ethanolamine Cholinephosphotransferase catalyses Cell healthphosphotransferase 1 the final step in the synthesis of Maintenancephosphatidylcholine by the transfer of Gene phosphocholine fromCDP-choline to diacylglycerol. The synthesis of phosphatidylethanolamineby ethanolaminephosphotransferase occurs using an analogous reaction.This gene codes for a choline/ethanolaminephosphotransferase. Theprotein can synthesize either choline- or ethanolamine-containingphospholipids. Phosphatidylcholine is a class of phospholipids called“essential phospholipids DSCR1 Down The DSCR1 (Adapt78) gene is Cellhealth syndrome transiently induced by stresses to Maintenance criticalregion temporarily protect cells against further Gene gene 1 potentiallylethal challenges. PAPOLA poly(A) Polymerase that creates the 3′ poly(A)Cell health polymerase tail of mRNA's. Also required for the Maintenancealpha endoribonucleolytic cleavage reaction at Gene some polyadenylationsites. HSBP1 heat shock exert cytoprotection and anti-apoptotic Cellhealth factor binding effects Maintenance protein 1 Gene METAP1methionyl Protein synthesis is initiated with a Cell healthaminopeptidase 1 methionine residue in eukaryotic cells or Maintenance aformylated methionine in prokaryotes, Gene mitochondria, andchloroplasts. For a large subset of proteins, the initiator methionineis cotranslationally removed before further posttranslationalmodification. The proteolytic removal of N-terminal methionine iscatalyzed by a family of enzymes known as methionine aminopeptidases(MetAPs). SGMS1 sphingomyelin Suppresses BAX-mediated apoptosis Cellhealth synthase 1 and also prevents cell death in response Maintenanceto stimuli such as hydrogen peroxide, Gene osmotic stress, elevatedtemperature and exogenously supplied sphingolipids. May protect againstcell death by reversing the stress-inducible increase in levels ofproapoptotic ceramide. Required for cell growth STK39 \serine STE20kinases involved in the regulation Cell health threonine of ionhomoeostasis and volume control Maintenance kinase 39 in mammalian cellsGene (STE20/SPS1 homolog, yeast)\“” VCL vinculin Involved in celladhesion. May be Cell health involved in the attachment of the actin-Maintenance based microfilaments to the plasma Gene membrane. May alsoplay important roles in cell morphology and locomotion. XPNPEP1\X-prolyl prolyl aminopeptidase (EC 3.4.11.9) is a Cell healthaminopeptidase proline-specific metalloaminopeptidase Maintenance(aminopeptidase that specifically catalyzes the removal of Gene P) 1,any unsubstituted N-terminal amino acid soluble\“” that is adjacent to apenultimate proline residue. Because of its specificity toward proline,it has been suggested that X- prolyl aminopeptidase is important in thematuration and degradation of peptide hormones, neuropeptides, andtachykinins, as well as in the digestion of otherwise resistant dietaryprotein fragments, thereby complementing the pancreatic peptidases.Deficiency of X- prolyl aminopeptidase results in excretion of largeamounts of imino- oligopeptides in urine NCAPD3 \non-SMC Regulatorysubunit of the condensin II Chomatin condensin II complex, a complexwhich establishes stability complex, mitotic chromosome architecture andis subunit D3\“” involved in physical rigidity of the chromatid axis.AOF2 amine a family of multiprotein corepressor Chromatin oxidase(flavin complexes that function through modification containing)modifying chromatin structure to keep domain 2 genes silent. Thepolypeptide composition of these complexes includes a common core of 2subunits, HDAC1 (601241)/HDAC2 (605164) and the FAD-binding proteinAOF2. functions as a histone demethylase and transcriptionalcorepressor, histone lysine-specific demethylase LSD1 interacts with p53(191170) to repress p53-mediated transcriptional activation, and toinhibit the role of p53 in promoting apoptosis. HMGN1 high-mobilityHMGN1 enhances the rate of heat Chromatin group shock-induced chromatinremodeling in modification nucleosome the HSP70 promoter, therebyleading to binding an increase in the levels of HSP70 domain 1transcripts during the early stages of heat shock induction. INOC1 INO80INOC1 defines a subfamily of Chromatin complex SWI2/SNF2 chromatinremodeling modification homolog 1 (S. cerevisiae) proteins. INOC1displayed ATPase activity specific to double-stranded DNA and exhibitedactivity on isolated human mononucleosomes. ATP hydrolysis ofdouble-stranded DNA occurred in a linear time course with a calculatedKm of 167 microM, similar to that of other ATPases of the SNF2/SWI2family. PCAF p300/CBP- Histone acetyltransferase; Functions as Chromatinassociated a histone acetyltransferase (HAT) to modification factorpromote transcriptional activation. Has significant histoneacetyltransferase activity with core histones (H3 and H4), and also withnucleosome core particles. RBBP4 retinoblastoma Core histone-bindingsubunit that may Chromatin binding target chromatin remodeling factors,modification protein 4 histone acetyltransferases and histonedeacetylases to their histone substrates in a manner that is regulatedby nucleosomal DNA. Component of several complexes which regulatechromatin metabolism. RCBTB1 regulator of May be involved in cell cycleregulation Chromatin chromosome by chromatin remodeling. modificationcondensation (RCC1) and BTB (POZ) domain containing protein 1 TOP2Btopoisomerase essential for mammalian neural Chromatin (DNA) IIdevelopment; catalyses topological modification beta 180 kDa genomicchanges essential for chromosome segregation, chromatin reorganization,TSN translin Translin and TRAX have been proposed Chromatin to beinvolved in DNA recombination, modification chromosomal translocationand mRNA transport and translation. TSNAX translin- Translin and TRAXhave been proposed Chromatin associated to be involved in DNArecombination, modification factor X chromosomal translocation and mRNAtransport and translation. TSPYL1 TSPY-like 1 chromatin remodelingfactor Chromatin modification UTX \ubiquitously Histone H3 methylationat Lys27 (H3K27 Chromatin transcribed methylation) is a hallmark ofsilent modification tetratricopeptide chromatin, dUTX, specificallyrepeat, X demethylates di- and trimethylated but chromosome\“” notmonomethylated H3K27, dUTX is intimately associated with activelytranscribed genes WAPAL wings apart- regulates heterochromatinorganization; Chromatin like homolog Wapl is a new regulator of sistermodification (Drosophila) chromatid resolution PHC3 polyhomeoticComponent of the Polycomb group Chromatin homolog 3 (PcG) multiproteinPRC1 complex, a modification (Drosophila) complex required to maintainthe transcriptionally repressive state of many genes, including Hoxgenes, throughout development. PcG PRC1 complex acts via chromatinremodeling and modification of histones; CDYL \chromodomain Proteinsencoded by this gene Chromatin protein, Y- superfamily possess achromodomain, a modification like\“” motif implicated in chromatinbinding and gene suppression, and a catalytic domain believed to beinvolved in histone acetylation. CENPJ centromere structural role forCPAP to maintain Chromatin protein J centrosome integrity and normalspindle modification morphology during cell division. TPK1 thiaminCofactor pyrophosphokinase 1 biosynthesis gene RFK riboflavin Cofactorkinase biosynthesis gene VNN1 vanin 1 VNN1 gene product is involved inthe Cofactor thymus homing of bone marrow cells biosynthesis and in lateadhesion steps of thymus gene homing under physiologic, noninflammatoryconditions. Recently VNN1 gene upregulation has been linked to increasedHDL level The product of CD1c gene is expressed on cortical thymocytes,immature myeloid dendritic cells, subset of normal peripheral B cellsand activated T cells P4HA1 \procollagen- When expressed intracellularlyor Collagen Tumor proline, 2- exogenously delivered, P4HA1 formationsuppressor oxoglutarate significantly inhibited tumor growth in activitygene activity 4- mice. Prolyl 4-hydroxylase (EC gene dioxygenase1.14.11.2) plays a central role in (proline 4- collagen synthesis. Itcatalyzes the hydroxylase), formation of 4-hydroxyproline in alphacollagens by hydroxylation of proline polypeptide residues in peptidelinkages. The 4- I\“” hydroxyproline residues are essential for thefolding of the newly synthesized procollagen polypeptide chain intotriple helical molecules. CHST2 carbohydrate CHST1 and CHST2 contributeto the Control of (N- generation of optimal L-selectin ligandsinflammation acetylglucosamine- in vascular endothelial cells at sitesof activity gene 6-O) inflammation and thus control sulfotransferase 2inflammation. PAPSS1 3′- 3′-phosphoadenosine 5′-phosphosulfateDetoxification phosphoadenosine (PAPS) synthase (PAPSS) catalyzes theActivity Gene 5′- biosynthesis of PAPS which serves as phosphosulfatethe universal sulfonate donor compound synthase 1 for allsulfotransferase reactions. PAPSS forms PAPS in two sequential steps.First inorganic sulfate combines with ATP to form adenosine 5′-phosphosulfate (APS) and pyrophosphate catalyzed by ATP sulfurylasedomain and in the second step, APS combines with another molecule of ATPto form PAPS and ADP catalyzed by APS kinase domain. The bifunctionalPAPSS1 is comprised of NH2-terminal APS kinase domain (approximately1-260 aa), and a COOH- terminal ATP sulfurylase domain (approximately220-623 aa).. Many different endogenous and xenobiotic molecules aresubstrates for the sulfotransferases; sulfation affects many differentphysiological processes, including: 1) deactivation and bioactivation ofxenobiotics, 2) inactivation of hormones and catecholamines, 3)structure and function of macromolecules, and 4) elimination of endproducts of catabolism. PAPS is the obligate cosubstrate that issynthesized in tissues to make available an “activated form” of sulfatefor the sulfation reaction. PPA2 pyrophosphatase Inorganicpyrophosphates are generated Detoxification (inorganic) 2 as byproductsof many biosynthetic Activity Gene reactions, including DNA and RNAsynthesis, fatty acid and amino acid activation, and cyclic nucleotidesynthesis. Inorganic pyrophosphatases (EC 3.6.1.1), such as PPA2,maintain the thermodynamic favorability of these reactions by catalyzingthe hydrolysis of pyrophosphates into organic phosphates, which are thenexported across the cell membrane (Curbo et al., 2006) RTN1 reticulon 1In the presence of high RTN-1C levels, Detoxification genotoxic drugsbecome ineffective as a Activity Gene consequence of the cytoplasmtranslocation of p53 protein, while the silencing of endogenous RTN-1Cresults in the potentiation of the genotoxic drugs action. Highlypresent in CNS. CNS stem cells? ATRN attractin in its natural serumform, it mediates the Detoxification mitochondrial spreading ofmonocytes that becomes Activity Gene, function the focus for theclustering of maintenance nonproliferating T lymphocytes. activityNecessary for proper mitochondrial gene function and suppress oxidativestress. Atrn may play a protective role against environmental toxinsPGK1 phosphoglycerate Glycolysis enzyme generating 1 Energy kinase 1molecule of ATP Generation GLS glutaminase human platelets. It is themajor enzyme Energy yielding glutamate from glutamine. generationSignificance of the enzyme derives from its possible implication inbehavior disturbances in which glutamate acts as a neurotransmitter.platelet glutaminase activity is entirely represented by the phosphatedependent glutaminase or glutaminase I, most probably localized in themitochondrial platelet fraction and classified by kinetic analysis as akidney- type form. The following step of the glutamine metabolizingpathway, allowing the entrance of the amino acid skeleton carbons in theKrebs cycle, might be catalyzed by both glutamate dehydrogenase andaspartate transaminase GLUD2 glutamate The following step of theglutamine Energy dehydrogenase 2 metabolizing pathway, allowing thegeneration entrance of the amino acid skeleton carbons in the Krebscycle, might be catalyzed by both glutamate dehydrogenase and aspartatetransaminase MUT methylmalonyl In mammalian cells only two enzymesEnergy Coenzyme A are known to require cobalamin (vitamin generationmutase B12) as a cofactor: methionine synthase, which usesmethylcobalamin, and methylmalonyl-coenzyme A (CoA) mutase, which uses5′-deoxyadenosyl- cobalamin (AdoCbl) Methylmalonyl-CoA mutase (MUT) (EC5.4.99.2) is a mitochondrial enzyme that catalyzes the isomerization ofmethylmalonyl-CoA to succinyl-CoA. Methylmalonyl-CoA mutase occupies akey position in the pathway converting propionyl-CoA to succinyl-CoA,with the catabolism of isoleucine, methionine, threonine, and valine, aswell as of cholesterol, odd chain fatty acids, thymine, and uracilleading to propionyl-CoA production. The enzyme is, therefore, part of agluconeogenic pathway for converting amino acids, lipids, andpyrimidines to carbohydrates PPAT phosphoribosyl PhosphopantetheineEnergy pyrophosphate adenylyltransferase (PPAT) is an generationamidotransferase essential enzyme in Coenzyme A biosynthesis.Biosynthesis of coenzyme A (CoA) from pantothenic acid (vitamin B5) isan essential universal pathway in prokaryotes and eukaryotes. COASY is abifunctional enzyme that catalyzes the 2 last steps in CoA synthesis.MTHFR \5,10- Methylenetetrahydrofolate reductase Homocysteinemethylenetetrahydrofolate (EC 1.5.1.20) catalyzes the conversionmetabolism reductase of 5,10-methylenetetrahydrofolate to 5- (NADPH)\“”methyltetrahydrofolate, a cosubstrate for homocysteine remethylation tomethionine. MTR 5- The remethylation of homocysteine to Homocysteinemethyltetrahydrofolate- form methionine is catalyzed by the metabolismhomocysteine cytoplasmic enzyme 5- methyltransferasemethyltetrahydrofolate-homocysteine S- methyltransferase (EC 2.1.1.13),which is also called methionine synthase. This enzyme requiresmethylcobalamin (MeCbl), a derivative of cobalamin, or vitamin B12, foractivity. MTRR 5- Methionine is an essential amino acid Homocysteinemethyltetrahydrofolate- required for protein synthesis and onemetabolism homocysteine carbon metabolism. Its synthesis ismethyltransferase catalyzed by the enzyme methionine reductase synthase.Methionine synthase eventually becomes inactive due to the oxidation ofits cob(l)alamin cofactor. The protein encoded by this gene regeneratesa functional methionine synthase via reductive methylation. It is amember of the ferredoxin-NADP(+) reductase (FNR) family of electrontransferases. ADCY7 adenylate Necessary for proper Eucaryotic signalImmune health cyclase 7 transduction in platelets and other bloodassociated cells including natural killer cells, monocytes, andneutrophils NCKAP1L NCK- Expressed only in cells of hematopoietic Immuneassociated origin. Health protein 1-like ABCB7 \ATP-binding essentialfor hematopoiesis Immune cassette, sub- Health family B (MDR/TAP),member 7\“” AHI1 Abelson expression of mouse and human AHI1 Immunehelper was highest in the most primitive types Health integration ofnormal hematopoietic cells and was site 1 downregulated during earlydifferentiation. This indicates that early precursors of blood cells arelikely present in the peripheral blood. CD164 \CD164 myeloid cells, Tcells, epithelial cells, Immune molecule, bone marrow stroma cells;adhesion Health sialomucin\“” molecule haem progenitor cells to stromaCD200 CD200 Normal brain and B-cell lines Immune molecule Health CD74\CD74 B cells, macrophages, monocytes, MHC Immune health molecule, classII positive cells major histocompatibility complex, class II invariantchain\“” CD83 CD83 Activated B cells, activated T cells, Immune healthmolecule circulating dendritic cells; CD8A CD8a The CD8 antigen is acell surface Immune health molecule glycoprotein found on most cytotoxicT lymphocytes that mediates efficient cell- cell interactions within theimmune system. The CD8 antigen, acting as a coreceptor, and the T-cellreceptor on the T lymphocyte recognize antigen displayed by an antigenpresenting cell (APC) in the context of class I MHC molecules. CytotoxicT cells (TC cells, or CTLs) destroy virally infected cells and tumorcells, and are also implicated in transplant rejection. These cells arealso known as CD8+ T cells, since they express the CD8 glycoprotein attheir surface. Through interaction with helper T cells, these cells canbe transformed into regulatory T cells, which prevent autoimmunediseases such as experimental autoimmune encephalomyelitis CERK ceramideCatalyzes specifically the Immune kinase phosphorylation of ceramide toform Health ceramide 1-phosphate. Ceramide 1- Phosphate, a Mediator ofPhagocytosis, might function as components of a ‘rheostat’ thatregulates immune cell functions, including mast cell responsiveness,neutrophil and macrophage priming, chemotaxis, and survival of manytypes of immune cells. CIAPIN1 cytokine CIAPIN1, a necessary moleculefor Immune induced hematopoiesis that mediates Health apoptosisantiapoptotic effects of various inhibitor 1 cytokines. CIITA \class II,Highly present in B-lymphocytes. This Immune health major gene encodes aprotein with an acidic histocompatibility transcriptional activationdomain, 4 complex, LRRs (leucine-rich repeats) and a GTP transactivator\binding domain. The protein is located in “” the nucleus and acts as apositive regulator of class II major histocompatibility complex genetranscription, and is referred to as the “master control factor” for theexpression of these genes. Mutations (lack of fuction) in this gene havebeen associated with bare lymphocyte syndrome type II (also known ashereditary MHC class II deficiency or HLA class II-deficient combinedimmunodeficiency), increased susceptibility to rheumatoid arthritis,multiple sclerosis, and possibly myocardial infarction. CLEC10A \C-typelectin Probable role in regulating adaptive and Immune domain familyinnate immune responses. Binds in a Health 10, member calcium-dependentmanner to terminal A\“” galactose and N-acetylgalactosamine units,linked to serine or threonine. CPNE3 copine III copine III wereexpressed in the more Immune immature neutrophil precursors Health CPVL\carboxypeptidase, CPVL protein expression was induced Immunevitellogenic- during maturation of monocytes into Health like\“”macrophages. CTNNB1 \catenin Hematopoietic stem cells (HSCs) have Immune(cadherin- the ability to renew themselves and to Health associated giverise to all lineages of the blood. protein), beta Reya et al. (2003)showed that the WNT 1, 88 kDa\“” signaling pathway has an important rolein this process. Overexpression of activated beta-catenin expands thepool of HSCs in long-term cultures by both phenotype and function,beta-catenin is essential for fate decisions of skin stem cells: in theabsence of beta-catenin, stem cells failed to differentiate intofollicular keratinocytes and instead adopted an epidermal fate CTSCcathepasin C Needed for activity and stability of Immuneneutrophil-derived serine proteases. Health CYFIP2 cytoplasmic Necessaryfor T-cell adhesion function Immune FMR1 Health interacting protein 2DPP8 dipeptidyl- involve in immune functions Immune peptidase 8 HealthDPP9 dipeptidyl- involve in immune functions Immune peptidase 9 HealthDPYSL2 dihydropyrimidinase- involved in T-cell polarization and Immunelike 2 migration. Health DUSP5 dual Mkp5-deficient cells producedgreatly Immune specificity enhanced levels of proinflammatory Healthphosphatase 5 cytokines during innate immune responses and exhibitedgreater T-cell activation than their wildtype counterparts. However,Mkp5-deficient T cells proliferated poorly upon activation, whichresulted in increased resistance to experimental autoimmuneencephalomyelitis. By contrast, Mkp5- deficient CD4+ (186940) and CD8+(186910) effector T cells produced significantly increased levels ofcytokines compared with wildtype cells, which led to much more robustand rapidly fatal immune responses to secondary infection withlymphocytic choriomeningitis virus. Zhang et al. (2004) concluded thatMKP5 has a principal function in both innate and adaptive immuneresponses. EDG1 \endothelial Adaptive immunity depends on T-cell Immunedifferentiation, exit from the thymus and T and B cells Healthsphingolipid travelling between secondary lymphoid G-protein- organs tosurvey for antigens. After coupled activation in lymphoid organs, Tcells receptor, 1\“” must again return to circulation to reach sites ofinfection; however, the mechanisms regulating lymphoid organ exit areunknown. S1P1-dependent chemotactic responsiveness is stronglyupregulated in T-cell development before exit from the thymus, whereasS1P1 is downregulated during peripheral lymphocyte activation, and thisis associated with retention in lymphoid organs. FCRL5 Fc receptor- Maybe involved in B-cell development Immune like 5 and differentiation inperipheral lymphoid Health organs and may be useful markers of B- cellstages. May have an immunoregulatory role in marginal zone B-cells. FERfer (fps/fes Fps/Fes modulates the innate immune Immune related)response of macrophages to LPS, in Health tyrosine part, by regulatinginternalization and kinase down-regulation of the TLR4 receptor(phosphoprotein complex. Fps/Fes and Fer are members NCP94) of adistinct subfamily of cytoplasmic protein tyrosine kinases that haverecently been implicated in the regulation of innate immunity, evidencefor functional redundancy between Fps and Fer kinases in regulatinghematopoiesis. FLT3 fms-related CD135 is a cytokine receptor expressedImmune tyrosine on the surface of hematopoietic Health kinase 3progenitor cells. Signaling through CD135 plays a role in cell survival,proliferation, and differentiation. CD135 is important for lymphocyte (Bcell and T cell) development, but not for the development of other bloodcells (myeloid development). NKTR natural killer- The natural killertriggering receptor Immune tumor (NKTR) is involved in the recognitionof Health recognition tumor cells by large granular sequence lymphocytes(LGLs) (Frey et al., 1991; Anderson et al., 1993). LGLs are asubpopulation of white blood cells that have the ability to kill targettumor cells by an MHC-independent mechanism. The protein product of theNKTR gene is present on the surface of LGLs and facilitates theirbinding to tumor targets. The gene codes for a protein of 150,000 Da,with a unique amino acid structure consisting of a 58-amino acidhydrophobic amino terminus followed by a cyclophilin-related domain.PABPC4 \poly(A) might be necessary for regulation of Immune bindingstability of labile mRNA species in Health protein, activated T cells.cytoplasmic 4 (inducible form)\“” PAG1 phosphoprotein Absence ofexternal stimuli, the PAG- Immune health associated Csk complextransmits negative with regulatory signals and thus may help toglycosphingolipid keep resting T cells in a quiescent state.microdomains 1 PAG-CSK complex increases the signaling thresholdrequired for initiating an immune response, thus helping to keeplymphocytes in a resting state. ADRBK2 \adrenergic, Specificallyphosphorylates the agonist- Immune health beta, receptor occupied formof the beta-adrenergic kinase 2\“” and closely related receptors, inleukocytes from patients with active relapsing-remitting multiplesclerosis (MS) or with secondary progressive MS, GRK2 levels aresignificantly reduced, probable role in immune Maintenance and healthGFI1 growth factor Gfi1 maintained hematopoietic stem cell Immune healthindependent 1 self-renewal, multilineage differentiation, and efficientreconstitution of hematopoiesis in transplanted hosts by restrictingstem cell proliferation GPR34 G protein- GPR34 is the functional mastcell lysoPS Immune health coupled receptor. Lysophosphatidyl-L-serinereceptor 34 (lysoPS) is thought to be an immunological regulator GPR44 Gprotein- This receptor also called, CRTH2 is a Immune health coupledreceptor for PGD2, PGD2 functions as a receptor 44 neuromodulator aswell as a trophic factor in the central nervous system. PGD2 is alsoinvolved in smooth muscle contraction/relaxation and is a potentinhibitor of platelet aggregation, receptor for prostaglandin (PG) D(2),which is a major mast cell product released during the allergicresponse. CRTH2 mediates the chemotaxis of eosinophils, basophils, andTh2 lymphocytes HHEX hematopoietically Transcriptional repressor. Mayplay a Immune health expressed role in hematopoietic differentiation.homeobox ID2 \inhibitor of Id2 has an essential role in the Immunehealth DNA binding generation of peripheral lymphoid 2, dominant organsand NK cells. D (inhibitor of DNA negative binding) HLH proteins lack abasic DNA- helix-loop- binding domain but are able to form helixprotein\“” heterodimers with other HLH proteins, thereby inhibiting DNAbinding, importance of Id2 in regulating gene expression by CD8(+) Tcells and the magnitude of effector responses, suggesting a mechanisminvolving Id protein- and E protein-mediated survival anddifferentiation of mature T cells, helix-loop-helix (HLH) transcriptionfactor Id2 (inhibitor of DNA binding/differentiation 2) acts as amolecular switch in development of Langerhans cells (LCs), the cutaneouscontingent of dendritic cells (DCs), and of specific DC subsets and Bcells. IL10RA \interleukin 10 The protein encoded by this gene is aImmune health receptor, receptor for interleukin 10. This protein isalpha\“” structurally related to interferon receptors. It has been shownto mediate the immunosuppressive signal of interleukin 10, and thusinhibits the synthesis of proinflammatory cytokines. This receptor isreported to promote survival of progenitor myeloid cells through theinsulin receptor substrate- 2/PI 3-kinase/AKT pathway. Activation ofthis receptor leads to tyrosine phosphorylation of JAK1 and TYK2kinases. IL7R interleukin 7 This protein has been shown to play a Immunehealth receptor critical role in the V(D)J recombination duringlymphocyte development. This protein is also found to control theaccessibility of the TCR gamma locus by STAT5 and histone acetylation.Knockout studies in mice suggested that blocking apoptosis is anessential function of this protein during differentiation and activationof T lymphocytes. The functional defects in this protein may beassociated with the pathogenesis of the severe combined immunodeficiency(SCID). Receptor for interleukin-7. Also acts as a receptor for thymicstromal lymphopoietin IRF8 interferon ICSBP in regulating theproliferation Immune health regulatory and differentiation ofhematopoietic factor 8 progenitor cells, antiviral responses associatedwith impaired production of IFN-gamma ITK IL2-inducible Tec kinases Itkand Rlk provide Immune health T-cell kinase important signals forterminal maturation, efficient cytokine production, and peripheralsurvival of NKT cells. This gene encodes an intracellular tyrosinekinase expressed in T-cells. The protein contains both SH2 and SH3domains which are often found in intracellular kinases. It is thought toplay a role in T- cell proliferation and differentiation. JAK1 Januskinase Tyrosine kinase of the non-receptor Immune health 1 (a proteintype, involved in the IFN- tyrosine alpha/beta/gamma signal pathway.kinase) Kinase partner for the interleukin (IL)-2 receptor. The Januskinase-signal transducer and activator of transcription (Jak-Stat)pathway stands as a paradigm of how diverse extracellular signals canelicit rapid changes in gene expression in specific target cells. Thispathway is widely used by members of the cytokine receptor superfamily,including those for the clinically important cytokines granulocytecolony- stimulating factor (G-CSF), erythropoietin, thrombopoietin, theinterferons, and numerous interleukins, which makes it central tohematopoietic cell biology and hematologic therapy alike. Impairedlymphoid development in the absensce of JAK1 JMJD1A jumonji Jmjd1a andJmjd2c histone H3 Lys 9 Immune health domain demethylases regulateself-renewal in containing 1A embryonic stem cells. JMJD2C jumonjiJmjd1a and Jmjd2c histone H3 Lys 9 Immune health domain demethylasesregulate self-renewal in containing 2C embryonic stem cells. KIR2DS2\killer cell Killer-cell immunoglobulin-like receptors Immune healthimmunoglobulin- (KIRs), are a family of cell surface like proteins foundon important cells of the receptor, two immune system called naturalkiller (NK) domains, cells. They regulate the killing function of shortthese cells by interacting with MHC class cytoplasmic I molecules, whichare expressed on all tail, 2\“” cell types. This interaction allows themto detect virally infected cells or tumor cells that have acharacteristic low level of Class I MHC on their surface. Most KIRs areinhibitory, meaning that their recognition of MHC suppresses thecytotoxic activity of their NK cell. Only a limited number of KIRs havethe ability to activate cells. This gene is an activating receptor.KLRC1 \killer cell Natural killer (NK) cells are lymphocytes Immunehealth lectin-like that can mediate lysis of certain tumor receptorcells and virus-infected cells without subfamily C, previous activation.They can also member 1\“” regulate specific humoral and cell- mediatedimmunity. NK cells preferentially express several calcium- dependent(C-type) lectins, which have been implicated in the regulation of NKcell function. L3MBTL3 l(3)mbt-like 3 H-L(3)MBT protein, whose deletionis Immune health (Drosophila) predicted to be responsible for myeloidhematopoietic malignancies, tumor suppressor gene. MEMO1 mediator ofHighly present in NK cells and other Immune health cell motility 1hematopoeitic cells NAGA \N- Highly present in monocytes (Ascenta)Immune health acetylgalactos what are the implications? lysosomalaminidase, glycohydrolase that cleaves alpha-N- alpha-\“”acetylgalactosaminyl moieties from glycoconjugates. NDFIP1 Nedd4 familyNdfip1 protein promotes the function of Immune health interacting itchubiquitin ligase to prevent T cell protein 1 activation and T helper 2cell-mediated inflammation. NR1D2 \nuclear Heme as the ligand Immunehealth receptor subfamily 1, group D, member 2\“” PRNP \prion proteinPrPc is expressed on hematopoietic Immune health Red blood (p27-30)cells, including erythroid precursors. cell health (Creutzfeldt- Prionprotein is expressed on long-term Jakob repopulating hematopoietic stemcells disease, and is important for their self-renewal. Gerstmann- PrPis a marker for long-term Strausler- hematopoietic stem cells. Prionprotein Scheinker expression may be involved in both the syndrome,metabolism of copper and resistance to fatal familial oxidative stress,neuroprotective role of insomnia)\“” cellular prion protein (PrPC) rionprotein interferes with divalent metal Mn uptake and protects againstMn-induced oxidative stress PSCD1 \pleckstrin Members of this familyappear to Immune health homology, mediate the regulation of proteinsorting Sec7 and and membrane trafficking. The PSCD1 coiled-coil ishighly expressed in natural killer and domains peripheral T cells, andregulates the 1(cytohesin adhesiveness of integrins at the plasma 1)\“”membrane of lymphocytes. PTGER4 prostaglandin This receptor can activateT-cell factor Immune health E receptor 4 signaling. It has been shown tomediate (subtype EP4) PGE2 induced expression of early growth response 1(EGR1), regulate the level and stability of cyclooxygenase-2 mRNA, andlead to the phosphorylation of glycogen synthase kinase-3. Knockoutstudies in mice suggest that this receptor may be involved in theneonatal adaptation of circulatory system, osteoporosis, as well asinitiation of skin immune responses. Receptor for prostaglandin E2(PGE2). The activity of this receptor is mediated by G(s) proteins thatstimulate adenylate cyclase. Has a relaxing effect on smooth muscle. Mayplay an important role in regulating renal hemodynamics, intestinalepithelial transport, adrenal aldosterone secretion, and uterinefunction. PTPN11 \protein Shp-2 is a widely expressed nonreceptor Immunehealth tyrosine protein tyrosine phosphatase that phosphatase,participates early in hematopoietic non-receptor development. type 11(Noonan syndrome 1)\“” PTPN22 \protein This gene encodes a proteintyrosine Immune health tyrosine phosphatase which is expressedphosphatase, primarily in lymphoid tissues. This non-receptor enzymeassociates with the molecular type 22 adapter protein CBL and may be(lymphoid)\“” involved in regulating CBL function in the T-cell receptorsignaling pathway. PTPRC \protein This gene is specifically expressed inImmune health tyrosine hematopoietic cells. This PTP has beenphosphatase, shown to be an essential regulator of T- receptor type, andB-cell antigen receptor signaling. It C\“” functions through eitherdirect interaction with components of the antigen receptor complexes, orby activating various Src family kinases required for the antigenreceptor signaling. This PTP also suppresses JAK kinases, and thusfunctions as a regulator of cytokine receptor signaling. RASSF5 RasPotential tumor suppressor. Seems to Immune health association beinvolved in lymphocyte adhesion by (RalGDS/AF- linking RAP1A activationupon T cell 6) domain receptor or chemokine stimulation to family 5integrin activation. Isoform 2 stimulates lymphocyte polarization andthe patch- like distribution of ITGAL/LFA-1, resulting in an enhancedadhesion to ICAM1. Together with RAP1A may participate in regulation ofmicrotubule growth. The association of isoform 2 with activated RAP1A isrequired for directional movement of endothelial cells during woundhealing RFX5 \regulatory MHC class II molecules play a key role Immunehealth factor X, 5 in the immune system. They present (influencesexogenous antigenic peptides to the HLA class II receptor of CD4+T-helper lymphocytes, expression)\“” thereby triggering theantigen-specific T- cell activation events required for the initiationand sustenance of immune responses.. Activates transcription from classII MHC promoters. Differentiation of hematopoietic stem and progenitorscells is an intricate process controlled in large part at the level oftranscription. new transcriptional regulators of megakaryopoiesis. SENP6SUMO1/sentrin important in adult hematopoietic self- Immune healthspecific renewal peptidase 6 SERPINB9 \serpin The intracellular granzymeB inhibitor, Immune health peptidase proteinase inhibitor 9, isup-regulated inhibitor, during accessory cell maturation and clade Beffector cell degranulation, and its (ovalbumin), overexpressionenhances CTL (cytotoxic member 9\“” lymphocyte) potency, the presenceand subcellular localization of PI-9 in leukocytes and DCs areconsistent with a protective role against ectopic or misdirected grBduring an immune response. SOX4 SRY (sex Sox4 contribute to the survivaland Immune health determining proliferation of pro-B cells in responseto region Y)-box 4 extracellular signals. SPEN \spen The ability of Ott1to affect Immune health homolog, hematopoietic cell fate and expansionin transcriptional multiple lineages is a novel attribute for regulatora spen family member and delineates (Drosophila)\“” Ott1 from otherknown effectors of hematopoietic development. SYBL1 synaptobrevin-VAMP-7 is a crucial component of Immune health like 1 granzyme B releaseand target cell killing in the NK cell TMPO thymopoietin It is possiblethat TCERG1 interacts with Immune health the nascent transcript (or RNP)and directly alters splicing decisions. This could be consistent withindependent effects on transcription elongation and alternativeprocessing. Alternatively, TCERG1 could work at VNN1 vanin 1 VNN1 geneproduct is involved in the Immune health thymus homing of bone marrowcells and in late adhesion steps of thymus homing under physiologic,noninflammatory conditions. Recently VNN1 gene upregulation has beenlinked to increased HDL level The product of CD1c gene is expressed oncortical thymocytes, immature myeloid dendritic cells, subset of normalperipheral B cells and activated T cells ZFX \zinc finger Zfx controlsthe self-renewal of Immune health protein, X- embryonic andhematopoietic stem cells. linked\“” Zfx as a shared transcriptionalregulator of ESC and HSC, suggesting a common genetic basis ofself-renewal in embryonic and adult SC. ZNF317 zinc finger ZNF317 mayplay an important role in Immune health Red blood protein 317 erythroidmaturation and lymphoid cell health proliferation ZNF589 zinc fingerCharacterization of SZF1 implicates its Immune health protein 589 rolein hematopoiesis. OGT O-linked N- The regulation of topoisomerase I(topo Immune acetylglucosamine I) activity is of prime importance forgene Health (GlcNAc) expression. It participates in DNA transferasereplication, transcription, recombination, (UDP-N- and DNA repair, andserves as a target acetylglucosamine: for anticancer drugs. Manyproteins and polypeptide- enzymes are modified by O-linked beta- N-N-acetylglucosamine (O-GlcNAc), which acetylglucosaminyl exerts profoundeffects on their function. transferase) OGT is a central factor for T-and B- lymphocytes activation.. OGT participation in intracellularglycosylation is essential for embryonic stem cell viability PIK3R1\phosphoinositide- Important in adult hematopoietic self- Immune3-kinase, renewal Health regulatory subunit 1 (p85 alpha)\“” NKRFNF-kappaB Interacts with a specific negative Inflammation repressingregulatory element (NRE) 5′- control factor AATTCCTCTGA-3′ to mediatetranscriptional repression of certain NK- kappa-B responsive genes.NF-κB- repressing factor (NRF) is a constitutively expressed nucleartranscription factor that binds to beta interferon (IFN-β),interleukin-8 (IL-8), and inducible nitric oxide synthase (iNOS)promoters and represses the basal transcription of these genes NR3C1\nuclear The glucocorticoid receptor (GR) is a Inflammation receptorligand-dependent transcription factor control subfamily 3, belonging tothe nuclear hormone group C, receptor superfamily. Due to its almostmember 1 ubiquitous expression, GR plays an (glucocorticoid importantrole in many physiological and receptor)\“” pathological processes.These include regulation of homeostasis, adaptation to stress, andmodulation of central nervous system. In addition, GR is a majormodulator of the immune system due to its proficient anti-inflammatoryand immunosuppressive activity; and its function is important for properregulation of many physiological processes. ZCCHC11 \zinc finger,ZCCHC11 is a unique TLR signal Inflammation CCHC regulator, whichinteracts with TIFA after control domain LPS treatment and suppressesthe containing TRAF6-dependent activation of NF- 11\“” kappaB. SIRT1sirtuin (silent Longevity gene Longevity mating type gene informationregulation 2 homolog) 1 (S. cerevisiae) YTHDF2 \YTH domain Apolymorphism of the YTHDF2 gene Longevity family, (1p35) located in anAlu-rich genomic gene member 2\“” domain is associated with humanlongevity. AP15 apoptosis Survival gene or anti-apoptotic gene Longevityinhibitor 5 gene ARNT aryl Bmal1-null mice lose circadian Longevityhydrocarbon rhythmicity but also display tendon gene receptorcalcification and decreased activity, nuclear body weight, and longevitytranslocator FRAP1 FK506 a gene expression signature associatedLongevity binding with mammalian target of rapamycin gene protein 12-(mTOR) activity that was down-regulated rapamycin with age but preservedby CR in both associated WAT and heart, mammalian cells the protein 1mammalian TOR (mTOR) pathway plays a significant role in determiningboth resting oxygen consumption and oxidative capacity, mTOR activitymay play an important role in determining the relative balance betweenmitochondrial and non-mitochondrial sources of ATP generation. HSPA9heat shock this member of the hsp70 family governs Longevity 70 kDaprotein the longevity of worms and thus there gene 9 (mortalin) arecommon pathways that determine mammalian and worm longevity POLG2\polymerase Mitochondrial polymerase processivity Mitochondrial (DNAsubunit. Stimulates the polymerase and DNA Health directed), exonucleaseactivities, and increases gamma 2, the processivity of the enzyme. Bindsto accessory sc-DNA. subunit\“” OPA1 optic atrophy Mitochondrial healthis defined by Mitochondrial 1 (autosomal various parameters includingfusion and Health dominant) fission events. In older cells, giantmitochondria accumulates. This is because of insufficient autophagy.These giants don't fuse with each other or with normal mitochondria andit was noticed that OPA1 is reduced in these giant mitochondria,mitochondria fuse and divide to change their morphology in response to amultitude of signals. During the past decade, work using yeast andmammalian cells has identified much of the machinery required for fusionand division, including the dynamin-related GTPases-- mitofusins (Fzo1pin yeast) and OPA1 (Mgm1p in yeast) for fusion and Drp1 (Dnm1p) fordivision. Mitochondrial fusion requires coordinated fusion of the outerand inner membranes. This process leads to exchange of contents,controls the shape of mitochondria, and is important for mitochondrialfunction. OPA1 is a major organizer of the mitochondrial inner membraneand is required for the maintenance of cristae integrity. As the loss ofOPA1 committed cells to apoptosis without any other stimulus. Olichon etal. (2003) proposed that OPA1 is involved in the sequestration ofcytochrome c, and that OPA1 may be a target for mitochondrial apoptoticeffectors. PDSS2 \prenyl PDSS2 gene, which encodes a subunitMitochondrial (decaprenyl) of decaprenyl diphosphate synthase, theHealth diphosphate first enzyme of the CoQ(10) biosynthetic synthase,pathway. subunit 2\“” MFN1 mitofusin 1 The regulated equilibrium betweenMitochondrial mitochondrial fusion and fission is Health essential tomaintain integrity of the organelle. Mechanisms of mitochondrial fusionare largely uncharacterized in mammalian cells. It is unclear whetherOPA1, a dynamin-related protein of the inner membrane mutated inautosomal dominant optic atrophy, participates in fusion or fission.OPA1 promoted the formation of a branched network of elongatedmitochondria, requiring the integrity of both its GTPase and C- terminalcoiled-coil domain. Stable reduction of OPA1 levels by RNA interferenceresulted in small, fragmented, and scattered mitochondria. Levels ofOPA1 did not affect mitochondrial docking, but they correlated with theextent of fusion as measured by polyethylene glycol mitochondrial fusionassays. A genetic analysis proved that OPA1 was unable to tubulate andfuse mitochondria lacking the outer membrane mitofusin 1 but notmitofusin 2. Our data show that OPA1 functionally requires mitofusin 1to regulate mitochondrial fusion and reveal a specific functionaldifference between mitofusin 1 and 2. MTRF1L mitochondrial Mitochondrialtranslational Health release factor 1-like NDUFC2 \NADH Accessorysubunit of the mitochondrial Mitochondrial dehydrogenase membranerespiratory chain NADH Health (ubiquinone) dehydrogenase (Complex I),that is 1, believed to be not involved in catalysis. subcomplex ComplexI functions in the transfer of unknown, 2, electrons from NADH to therespiratory 14.5 kDa\“” chain. The immediate electron acceptor for theenzyme is believed to be ubiquinone. NDUFS1 \NADH Core subunit of themitochondrial Mitochondrial dehydrogenase membrane respiratory chainNADH Health (ubiquinone) dehydrogenase (Complex I) that is Fe—S proteinbelieved to belong to the minimal 1.75 kDa assembly required forcatalysis. (NADH- Complex I functions in the transfer of coenzyme Qelectrons from NADH to the respiratory reductase)\“” chain. Theimmediate electron acceptor for the enzyme is believed to be ubiquinone(By similarity). This is the largest subunit of complex I and it is acomponent of the iron-sulfur (IP) fragment of the enzyme. It may formpart of the active site crevice where NADH is oxidized. SDHD \succinateComplex II of the respiratory chain, Mitochondrial dehydrogenase whichis specifically involved in the Health complex, oxidation of succinate,carries electrons subunit D, from FADH to CoQ. The complex is integralcomposed of four nuclear-encoded membrane subunits and is localized inthe protein\“” mitochondrial inner membrane. ENC1 ectodermal- Highlypresent in neuronal cells (and Nervous neural cortex brain tissues fromAscenta-almost System Health (with BTB-like absent in other tissues) andinvolved in domain) neuronal differentiation. Likely a Redox controllingprotein ADNP activity- Involved in proper lipid metabolism, Nervousdependent coagulation as well as in neurogenesis. System Healthneuroprotector Multiple Roles in Neuronal Differentiation andMaintenance, neuroprotective protein AGTPBP1 ATP/GTP zinccarboxypeptidase that contains Nervous binding nuclear localizationsignals and an System Health protein 1 ATP/GTP-binding motif that wasinitially cloned from regenerating spinal cord neurons of the mouse.Role in preventing neurodegeneration. OAT ornithine OAT encodes themitochondrial enzyme Nervous aminotransferase ornithineaminotransferase, which is a system health (gyrate key enzyme is thepathway that converts atrophy) arginine and ornithine into the majorexcitatory and inhibitory neurotransmitters glutamate and GABA. VitaminB6 dependent enzyme. PTDSS1 Phosphatidylserine Phosphatidylserine (PS orPtdSer) is a Nervous synthase 1 phospholipid nutrient found in fish,green system health leafy vegetables, soybeans, and rice, and isessential for the normal functioning of neuronal cell membranes,activating protein kinase C (PKC), which has been shown to be involvedin memory function. PS has been investigated in a small number ofdouble-blind placebo trials and has been shown to increase memoryperformance in the elderly. Because of the potential cognitive benefitsof phosphatidylserine, the substance is sold as a dietary supplement topeople that believe they can benefit from an increased intake. SPOCK2\sparc/osteonectin, May participate in diverse steps of Nervous cwcvneurogenesis system health and kazal-like domains proteoglycan(testican) 2\“” ADSS adenylosuccinate carries out the first of a 2-stepsequence Nucleotide synthase in the biosynthesis of AMP from IMP.Biosynthesis Plays an important role in the de novo pathway of purinenucleotide biosynthesis. AMP, is a nucleotide that is found in RNA. DCTDdCMP Supplies the nucleotide substrate for Nucleotide deaminasethymidylate synthetase which is the Biosynthesis enzyme used to generatethymidine monophosphate (dTMP), which is subsequently phosphorylated tothymidine triphosphate for use in DNA synthesis and repair. HPRT1hypoxanthine HPRT1 has a central role in the Nucleotidephosphoribosyltransferase generation of purine nucleotides throughbiosynthesis 1 (Lesch- the purine salvage pathway. HPRT1 Nyhan catalyzesconversion of hypoxanthine to syndrome) inosine monophosphate andguanine to guanosine monophosphate via transfer of the 5-phosphoribosylgroup from 5- phosphoribosyl 1-pyrophosphate PRPS1 phosphoribosylPhosphoribosylpyrophosphate Nucleotide pyrophosphate synthetase (PRPS;EC 2.7.6.1) biosynthesis synthetase 1 catalyzes the phosphoribosylationof ribose 5-phosphate to 5-phosphoribosyl- 1-pyrophosphate, which isnecessary for the de novo and salvage pathways of purine and pyrimidinebiosynthesis CMPK cytidylate Uridine monophosphate (UMP)/cytidineNucleotide Mitochondrial kinase monophosphate (CMP) kinase (ECBiosynthesis Health 2.7.4.4) catalyzes the phosphoryl transfer from ATPto UMP, CMP, and deoxy-CMP (dCMP), resulting in the formation of ADP andthe corresponding nucleoside diphosphate. These nucleoside diphosphatesare required for cellular nucleic acid synthesis. Enzyme deficiency inthe salvage pathway of deoxyribonucleotide synthesis in mitochondria cancause mtDNA depletion syndromes. Maintenance of mitochondrial health.ABCD3 \ATP-binding Peroxisome biogenesis Peroxisome cassette, sub-Health family D (ALD), member 3\“” ABCD4 \ATP-binding Peroxisomebiogenesis Peroxisome cassette, sub- Health family D (ALD), member 4\“”PEX12 peroxisomal Peroxisome biogenesis Health factor 12 PEX3peroxisomal Peroxisome biogenesis Health factor 3 RABGAP1L RAB GTPaseLower levles in platelet dysfunction Platelet health activating protein1-like CANX calnexin Calcium-binding protein that interacts Proteinquality with newly synthesized glycoproteins in control the endoplasmicreticulum. It may act in assisting protein assembly and/or in theretention within the ER of unassembled protein subunits. It seems toplay a major role in the quality control apparatus of the ER by theretention of incorrectly folded proteins. CLPX ClpX Clp ATPases areprotein machines Protein quality caseinolytic involved in proteindegradation. The control peptidase X ClpXP ATPase-protease complex is ahomolog (E. coli) major component of the protein quality controlmachinery in the cell. DERL1 \Der1-like Derlin-1 is an important factorfor the Protein quality domain extraction of certain aberrantly foldedcontrol family, proteins from the mammalian ER. member 1\“” Functionalcomponent of endoplasmic reticulum-associated degradation (ERAD) formisfolded lumenal proteins. May act by forming a chann DNAJA1 \DnaJHuman DnaJ 2 (Hdj-2) is a co- Protein quality (Hsp40) chaperone of heatshock cognate 70 control homolog, (Hsc70) which is localized to thesubfamily A, cytosolic face of the ER. Necessary for member 1\“” properfolding of proteins and therefore proper functions of various proteins.EDEM3 \ER enhances glycoprotein endoplasmic Protein quality degradationreticulum-associated degradation and control enhancer, mannose trimming,accelerates ERAD of mannosidase misfolded glycoproteins. alpha-like 3\“”OMA1 \OMA1 The integrity of the inner membrane of Protein qualityhomolog, zinc mitochondria is maintained by a control metallopeptidasemembrane-embedded quality control S. cerevisiae)\ system that ensuresthe removal of “” misfolded membrane proteins. Two ATP-dependent AAAproteases with catalytic sites at opposite membrane surfaces are keycomponents of this proteolytic system, identify Oma1 as a novelcomponent of the quality control system in the inner membrane ofmitochondria. Mitochondrial protease CTSO cathepsin O normal cellularprotein degradation and Protein quality tumover control HSP90AB1 \heatshock HSP90's function in the regulation and Protein quality protein 90kDa correct folding of at least 100 control alpha proteins[26] allows itto refold and/or (cytosolic), degrade these products before they class Btrigger cell death. They participate in the member 1\“” regulation ofthe stress response [2, 3] and, when associated with other co-chaperones, function in correctly folding newly synthesized proteins,stabilizing and refolding denatured proteins after stress, preventingmisfolding and aggregation of unfolded or partially folded proteins, andassisting in protein transport across the endoplasmic reticulum (ER) andorganellar membranes [4-8]. HSP90 members have key roles in thematuration of signal transduction proteins, like hormone receptors,various kinases, nitric oxide synthase and calcineurin HSPBAP1 HSPB(heat Protein quality shock 27 kDa) control associated protein 1 NGLY1N-glycanase 1 N-glycanase is a highly conserved Protein quality enzymethat catalyzes deglycosylation control of misfolded N-linkedglycoproteins by cleaving the glycan chain before the proteins aredegraded by the proteasome SACS spastic ataxia The presence ofheat-shock domains Protein quality of Charlevoix- suggested a functionfor sacsin in control Saguenay chaperone-mediated protein folding.(sacsin) SELS selenoprotein S SEPS1 gene helps in ridding the cell ofProtein quality misfolded proteins, preventing it from controlaccumulating and subsequently resulting to inflammation. SEPS1 as a typeof “garbage truck” that helps clear faulty proteins that accumulate incells when they are placed under stress, causing inflammation todevelop. ST13 suppression Hip facilitates may facilitate the Proteinquality of chaperone function of Hsc/Hsp70 in control tumorigenicityprotein folding and repair, and in 13 (colon controlling the activity ofregulatory carcinoma) proteins such as steroid receptors and (Hsp70regulators of proliferation or apoptosis. interacting protein) PDIA6\protein Formation and rearrangement of Protein quality disulfidedisulfide bonds during the correct folding control isomerase of nascentproteins is modulated by a family A, family of enzymes known as thiolmember 6\“” isomerases, which include protein disulfide isomerase (PDI),PDCL phosducin-like most members of the phosducin family Protein qualityact as co-chaperones with the cytosolic control chaperonin complex (CCT)to assist in the folding of a variety of proteins from their nascentpolypeptides PDCL3 phosducin-like 3 most members of the phosducin familyProtein quality act as co-chaperones with the cytosolic controlchaperonin complex (CCT) to assist in the folding of a variety ofproteins from their nascent polypeptides AGA aspartylglucos key enzymein the catabolism of N- Protein quality; aminidase linkedoligosaccharides of glycoproteins. Nervous It cleaves the asparaginefrom the system health residual N-acetylglucosamines as one of the finalsteps in the lysosomal breakdown of glycoproteins. Needed for properfolding of proteins, particularly in the nervous system ABCB10\ATP-binding a mitochondrial inner membrane Red blood cell cassette,sub- erythroid transporter involved in heme health family B biosynthesis(MDR/TAP), member 10\“” CAPRIN2 caprin family Involved in regulation ofgrowth as Red blood cell member 2 erythroblasts shift from a highlyhealth proliferative state towards their terminal phase ofdifferentiation. CYBRD1 cytochrome b Cybrd1 (duodenal cytochrome b) isnot Red blood cell reductase 1 necessary for dietary iron absorption inhealth mice. Likely participates in enhanced iron demand due toerythropoesis, ay be involved in extracellular ascorbate recycling inerythrocyte membranes. EDRF1 Erythroid Transcription factor involved inerythroid Red blood cell differentiation- differentiation. Involved intranscriptional health related activation of the globin gene. factor 1ERMAP erythroblast Human Ermap is highly expressed in Red blood cellmembrane- erythroid tissues and the protein health associated localizesto the plasma membrane, protein particularly in sites of cell contact,and (Scianna “cytoplasmic bodies.” Ermap expression blood group) wasrestricted to fetal and adult erythroid tissues ETS1 v-ets ETS isresponsible for erythroblast and Red blood cell Immune erythroblastosfibroblast transformation. Critical for health Health is virus E26maturation of the T Cells. Tumor oncogene suppressor. homolog 1 (avian)FLVCR1 feline Exports cytoplasmic heme. May be Red blood cell leukemiavirus required to protect developing erythroid health subgroup C cellsfrom heme toxicity. cellular receptor 1 ADD3 adducin 3 ADD3 may have arole in erythroblasts Red blood cell (gamma) and play an earlier role inerythropoiesis, health hypertension. IKZF1 IKAROS structure of achromatin remodeling Red blood cell family zinc complex (PYR complex)with Ikaros as health finger 1 its DNA binding subunit that is (Ikaros)specifically present in adult murine and human hematopoietic cells.Ikaros is involved in human adult or fetal erythroid differentiation aswell as in the commitment between erythroid and myeloid cells. MAEAmacrophage The association of erythroblasts with Red blood cellerythroblast macrophages plays a central role in the health attacherterminal maturation and enucleation of erythroblasts. MAEA mediatesattachment of erythroblasts to macrophages. MYB v-myb c-Myb is strictlyrequired for expression Red blood cell myeloblastosis of the c-Kitreceptor in erythroid cells. health viral The transcription factor c-Mybis oncogene expressed at high levels in immature homolog progenitors ofall hematopoietic lineages (avian) and is involved in the regulation ofproliferation, differentiation, and survival, role for c-Myb as a factorpromoting commitment to erythropoiesis and progression from early tolate stages of differentiation (FIG. 6). We have shown that thisfunction of c-Myb is probably not related to the cell cycle but ratherto the control of a network of hematopoietic regulators. The expressionof c-Kit in erythroid progenitors was tightly dependent on c- Myblevels. Finally, we demonstrated that c-Myb acts as a coordinator at theCFU-E stage by promoting further progression while supporting terminalcell divisions. NFE2L3 nuclear factor Activates erythroid-specific,globin gene Red blood cell (erythroid- expression health derived 2)-like3 SMAP1 stromal SMAP-1 may have a stimulatory effect Red blood cellmembrane- on stroma-supported erythropoiesis. health associated protein1 ZNF266 zinc finger HZF1 play important roles in erythroid Red bloodcell protein 266 and megakaryocytic differentiation. health IncreasedHZF1 mRNA expression was observed following erythroid differentiation ofK562 cells induced by hemin or megakaryocytic differentiation of K562cells induced by phorbol myristate acetate (PMA). Both of the antisensemethod and RNA interference assay revealed that RNPS1 \RNA bindingFormation of transcription-induced R- RNA Quality protein S1, loopsposes a critical threat to genomic Control serine-rich integritythroughout evolution., RNA domain\“” binding protein RNPS1 alleviatesASF/SF2 depletion-induced genomic instability. RNPS1, that whenoverexpressed strongly suppresses the high molecular weight (HMW) DNAfragmentation, hypermutation, and G2 cell cycle arrest phenotypes ofASF/SF2- depleted cells. Involved in RENT2- dependent nonsense-mediateddecay (NMD) of mRNAs containing premature stop codons. Also mediatesincrease of mRNA abundance and translational efficiency. Binds splicedmRNA 20-25 nt upstream of exon-exon junctions, low NMD efficiency isshown to be functionally related to the reduced abundance of the exonjunction component RNPS1 PAPOLG poly(A) This gene encodes a member ofthe RNA Quality polymerase poly(A) polymerase family which Control gammacatalyzes template-independent extension of the 3′ end of a DNA/RNAstrand. This enzyme is exclusively localized in the nucleus and exhibitsboth nonspecific and CPSF (cleavage and polyadenylation specificityfactor)/AAUAAA-dependent polyadenylation activity. DCP2 DCP2 Necessaryfor the degradation of RNA Quality decapping mRNAs, both in normal mRNAtumover Control enzyme and in nonsense-mediated mRNA homolog (S.cerevisiae) decay. DDX5 DEAD (Asp- Nonsense mediated RNA degradation RNAQuality Glu-Ala-Asp) Control box polypeptide 5 ERLIN2 ER lipid raft keyERAD pathway component that may RNA Quality associated 2 act as asubstrate recognition factor. Control PARN pol(A)- 3′-exoribonucleasethat has a preference RNA quality specific for poly(A) tails of mRNAs,thereby control ribonuclease efficiently degrading poly(A) tails.(deadenylation Exonucleolytic degradation of the nuclease) poly(A) tailis often the first step in the decay of eukaryotic mRNAs and is alsoused to silence certain maternal mRNAs translationally during oocytematuration and early embryonic development. Interacts with both the3′-end poly(A) tail and the 5′-end cap structure during degradation, theinteraction with the cap structure being required for an efficientdegradation of poly(A) tails. Involved in nonsense-mediated mRNA decay,a critical process of selective degradation of mRNAs that containpremature stop codons. UPF2 UPF2 Nonsense-mediated mRNA decay RNAquality regulator of (NMD) represents a key mechanism to controlnonsense control the expression of wild-type and transcripts aberrantmRNAs. Phosphorylation of the homolog protein UPF1 in the context of(yeast) translation termination contributes to committing mRNAs to NMD.UPF3A UPF3 They promote nonsense-mediated RNA quality regulator of mRNAdecay (NMD), and they also control nonsense regulate translationefficiency. transcripts homolog A (yeast) TRNT1 \tRNA Adds and repairsthe conserved 3′-CCA RNA quality nucleotidyl sequence necessary for theattachment control transferase, of amino acids to the 3′ terminus ofCCA-adding, tRNA molecules, using CTP and ATP as 1\“” substrates. MAT2B\methionine Methionine adenosyltransferase (MAT; SAM adenosyltransferaseS-adenosyl-L-methionine synthetase, Biosynthetic II, EC 2.5.1.6)1 is anessential enzyme that machinary beta\“” catalyzes the synthesis of S-adenosylmethionine (AdoMet) from L- methionine (L-Met) and ATP (1, 2).AdoMet is the major methyl group donor, participating in the methylationof proteins, DNA, RNA, phospholipids, and other small molecules(reviewed in Refs. 3-5). In addition, AdoMet is the ultimate source ofthe propylamine moiety used in polyamine biosynthesis, and it serves asco-factor for other key enzymes in the one-carbon metabolism pathway.Methionine adenosyltransferase (MAT; EC 2.5.1.6) catalyzes thebiosynthesis of S-adenosylmethionine (AdoMet) from methionine and ATP.MAT II is a broadly expressed MAT consisting of catalytic alpha andnoncatalytic beta subunits encoded by MAT2A (601468) and MAT2B,respectively. Methionine adenosyltransferase (MAT) catalyzes thebiosynthesis of S- adenosylmethionine (AdoMet), a key molecule intransmethylation reactions and polyamine biosynthesis. The MAT IIisozyme consists of a catalytic alpha2 and a regulatory beta subunit.Down- regulation of the MAT II beta subunit expression causes a6-10-fold increase in intracellular AdoMet levels. SKIV2L2 superkillermutation in skiv2l2 causes defects in cell Skin Health viralicidicproliferation, suggesting that skiv2l2 activity 2-like plays a role inregulating melanoblast 2 (S. cerevisiae) proliferation during earlystages of melanocyte regeneration. Skin ALDH18A1 \aldehyde Defects inthis enzyme plays a role in Skin health, Nervous dehydrogenaseneurodegeneration, joint laxity, skin system 18 family, hyperelasticity.Role in L-Proline health member A1\“” biosynthesis KIT Mast/stem cellmobilization of hematopoetic stem cells Stem cell growth factor intoperipheral blood; marker for HSCs health receptor and MSCs precursorFLT3 FMS-like restricted to CD34+ (high proportion of Stem cell tyrosinestem/progenitor cells) health kinase 3) ITK IL2-inducible play a role inT cell proliferation and Stem cell T-cell kinase differentiation healthCD74 Cluster of Hematopoietic Stem Cell survival Stem cellDifferentiation pathway health 74 HOXB2 Homeobox Expressed inerythromegakaryocytic Stem cell B2, cells and Hematopoietic Stem Cellshealth CIAPIN1 Cytokine Necessary for hematopoiesis Stem cell inducedhealth apoptosis inhibitor 1 NOTCH4 hematopoietic stem/progenitor cellsStem cell health NCOR1 nuclear NCOR, a repressor or transcription, is aStem cell receptor co- principal regulator in neural stem cells healthrepressor 1 PUM2 pumilio Sequence-specific RNA-binding protein Stem cellhomolog 2 that regulates translation and mRNA health (Drosophila)stability by binding the 3′-UTR of mRNA targets. Its interactions andtissue specificity suggest that it may be required to supportproliferation and self- renewal of stem cells by regulating thetranslation of key transcripts. SLAIN2 \SLAIN motif Slain1 was expressedat the stem cell Stem cell family, and epiblast stages of ESC healthmember 2\“” differentiation ACVR1 \activin A Necessary for properskeletal/bone Stem cell receptor, type formation; regulate the fate ofhealth I\“” hematopoietic progenitor and stem cells during developmentPDCD4 programmed The translation inhibitor programmed cell Tumor celldeath 4 death 4 (Pdcd4) suppresses suppresor (neoplastic tumorigenesisand invasion. transformation inhibitor) AXIN2 \axin 2 The Axin-relatedprotein, Axin2, Tumor (conductin, presumably plays an important role insuppressor axil)\“” the regulation of the stability of beta- functioncatenin in the Wnt signaling pathway, like its rodent homologs, mouseconductin/rat axil. In mouse, conductin organizes a multiprotein complexof APC (adenomatous polyposis of the colon), beta-catenin, glycogensynthase kinase 3-beta, and conductin, which leads to the degradation ofbeta-catenin. Apparently, the deregulation of beta- catenin is animportant event in the genesis of a number of malignancies. The AXIN2gene has been mapped to 17q23-q24, a region that shows frequent loss ofheterozygosity in breast cancer, neuroblastoma, and other tumors.Mutations in this gene have been associated with colorectal cancer withdefective mismatch repair. AZIN1 antizyme It has been shown to regulateDNA Tumor inhibitor 1 methylation and has tumor suppressor suppressoractivity, enhances the nonhomologous function end-joining repair of DNAdouble-strand breaks in human oral cancer cells. BECN1 \beclin 1 UVRAGinteracts with Beclin 1, leading Tumor (coiled-coil, to activation ofautophagy and thereof suppressor myosin-like inhibition oftumorigenesis. function BCL2 interacting protein)\“” CREBBP CREB bindingCBP has tumor suppressing activity. CBP Tumor protein may function as a‘master-switch’ suppressor (Rubinstein- between energy storage andfunction Taybi expenditure, long term memory. syndrome) CREBL2 cAMPpotential tumor suppressor Tumor responsive suppressor element functionbinding protein-like 2 DIDO1 death inducer- Putative transcriptionfactor, weakly pro- Tumor obliterator 1 apoptotic when overexpressed (Bysuppressor similarity). Tumor suppressor. function ING2 \inhibitor ofTumor suppressor Tumor growth family, suppressor member 2\“” functionKRAS v-Ki-ras2 Pfeifer (2001) noted an interesting Tumor Kirsten ratparallel to the p53 (191170) tumor suppressor sarcoma viral suppressor,which was initially described function oncogene as an oncogene, carryingpoint homolog mutations in tumors. Later it was discovered that it is,in fact, the wildtype copy of the gene that functions as a tumorsuppressor gene and is capable of reducing cell proliferation MTSS1metastasis putative metastasis suppressor gene Tumor suppressor 1suppressor function RB1 retinoblastoma Key regulator of entry into celldivision Tumor 1 (including that acts as a tumor suppressor. Directlysuppressor osteosarcoma) involved in heterochromatin formation byfunction maintaining overall chromatin structure and, in particular,that of constitutive heterochromatin by stabilizing histone methylation.SDCCAG1 serologically can function as a tumor suppressor in Tumordefined colon human lung cancer cells. suppressor cancer functionantigen 1 SMAD4 SMAD family Common mediator of signal transduction Tumormember 4 by TGF-beta (transforming growth suppressor factor)superfamily; SMAD4 is the function common SMAD (co-SMAD). Promotesbinding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides anactivation function required for SMAD1 or SMAD2 to stimulatetranscription. May act as a tumor suppressor. STK3 \serine/threonineNovel tumor suppressor function. Tumor kinase 3 Stress-activated,pro-apoptotic kinase suppressor (STE20 which, followingcaspase-cleavage, function homolog, enters the nucleus and inducesyeast)\“” chromatin condensation followed by internucleosomal DNAfragmentation. UVRAG UV radiation UVRAG interacts with Beclin 1, leadingTumor resistance to activation of autophagy and thereof suppressorassociated inhibition of tumorigenesis. function gene WWOX WW domaincritical tumor suppressor gene Tumor containing suppressoroxidoreductase function FOXO1 forkhead box Tumor suppressor andessential role in Tumor Immune O1 the Maintenance of hematopoetic stemsuppressor Health cells function TFRC \transferrin receptor (p90,CD71)\“”

1. A method for modulating the expression of genes related to chromatinstability in a subject in need thereof, the method comprising:administering to the subject an effective amount of a compositioncomprising a fruit ingredient, a vegetable ingredient and an herbalingredient, wherein the fruit ingredient is pomegranate, present in adosage range of about 5 mg/day to about 500 mg/day, and citrusbioflavonoids, present in a dosage range of about 25 mg/day to about1000 mg/day, wherein the vegetable ingredient is asparagus, present in adosage range of 25 mg/day to about 1000 mg/day, and watercress, presentin a dosage range of about 5 mg/day to about 500 mg/day, and wherein theherbal ingredient is oregano, present in a dosage range of 25 mg/day toabout 1000 mg/day, and rosemary, present in a dosage range of 25 mg/dayto about 1000 mg/day; whereby the expression of genes related tochromatin stability is modulated.
 2. The method of claim 1, wherein saidadministering step includes administering the composition to a subjectin the form of three tablets, each tablet administered twice a day. 3.The method of claim 1, wherein said modulating step includesup-regulating the expression of chromatin stability-related genes.
 4. Amethod of modulating the expression of DNA repair-related genes in asubject in need thereof, the method comprising: administering to thesubject an effective amount of a composition comprising a fruitingredient, a vegetable ingredient and an herbal ingredient, wherein thefruit ingredient is pomegranate, present in a dosage range of about 5mg/day to about 500 mg/day, and citrus bioflavonoids, present in adosage range of about 25 mg/day to about 1000 mg/day, wherein thevegetable ingredient is asparagus, present in a dosage range of 25mg/day to about 1000 mg/day, and watercress, present in a dosage rangeof about 5 mg/day to about 500 mg/day, and wherein the herbal ingredientis oregano, present in a dosage range of 25 mg/day to about 1000 mg/day,and rosemary present in a dosage range of 25 mg/day to about 1000mg/day; whereby the expression of genes related to DNA repair ismodulated.
 5. The method of claim 4, wherein said administering stepincluding administering the composition to a subject in the form ofthree tablets, each tablet administered twice a day.
 6. The method ofclaim 4, wherein said modulating step includes up-regulating theexpression of DNA repair-related genes.
 7. A method for reducing therisk of chromatin damage, the method comprising: administering aneffective amount of a composition comprising a fruit ingredient, avegetable ingredient and an herbal ingredient, wherein the fruitingredient is pomegranate, present in a dosage range of about 5 mg/dayto about 500 mg/day, and citrus bioflavonoids, present in a dosage rangeof about 25 mg/day to about 1000 mg/day, wherein the vegetableingredient is asparagus, present in a dosage range of 25 mg/day to about1000 mg/day, and watercress, present in a dosage range of about 5 mg/dayto about 500 mg/day, and wherein the herbal ingredient is oregano,present in a dosage range of 25 mg/day to about 1000 mg/day, androsemary present in a dosage range of 25 mg/day to about 1000 mg/day;and modulating the expression of genes to reduce the risk of chromatindamage with the administered effective amount of the composition.
 8. Themethod of claim 7, wherein said administering step includingadministering the composition to a subject in the form of three tablets,each tablet administered twice a day.
 9. The method of claim 7, whereinsaid modulating step includes up-regulating the expression of chromatinstability-related genes.